Novel Pharmaceutical Compounds

ABSTRACT

The instant invention provides compounds of Formula (Ia) which are leukotriene biosynthesis inhibitors, wherein X is O or S, Y is O, S, —NR 6 —CHR 7 — or —NR 8 —C(O)— and A is selected from 5-membered aromatic heterocyclic ring, 6-membered aromatic heterocyclic ring, naphthelenic or heterobicyclic aromatic ring system, phenyl and benzyl. A is optionally mono- or disubstituted. Compounds of Formula (Ia) are useful as anti-atherosclerotic, anti-asthmatic, anti-allergic, anti-inflammatory and cytoprotective agents.

FIELD OF THE INVENTION

The instant invention involves novel compounds which are useful asinhibitors of leukotriene biosynthesis.

BACKGROUND OF THE INVENTION

Inhibition of leukotriene biosynthesis has been an active area ofpharmaceutical research for many years. The leukotrienes constitute agroup of locally acting hormones, produced in living systems fromarachidonic acid. Leukotrienes are potent contractile and inflammatorymediators derived by enzymatic oxygenation of arachidonic acid by5-lipoxygenase. One class of leukotriene biosynthesis inhibitors arethose known to act through inhibition of 5-lipoxygenase (5-LO).

The major leukotrienes are Leukotriene B₄ (abbreviated as LTB₄), LTC₄,LTD₄ and LTE₄. The biosynthesis of these leukotrienes begins with theaction of the enzyme 5-lipoxygenases on arachidonic acid to produce theepoxide known as Leukotriene A₄ (LTA₄), which is converted to the otherleukotrienes by subsequent enzymatic steps. Further details of thebiosynthesis as well as the metabolism of the leukotrienes are to befound in the book Leukotrienes and Lipoxygenases, ed. J. Rokach,Elsevier, Amsterdam (1989). The actions of the leukotrienes in livingsystems and their contribution to various diseases states are alsodiscussed in the book by Rokach.

In general, 5-LO inhibitors have been sought for the treatment ofallergic rhinitis, asthma and inflammatory conditions includingarthritis. One example of a 5-LO inhibitor is the marketed drug zileuton(ZYLOFT®) which is indicated for the treatment of asthma. More recently,it has been reported that 5-LO may be an important contributor to theatherogenic process; see Mehrabian, M. et al., Circulation Research,2002 Jul. 26, 91(2):120-126.

Despite significant therapeutic advances in the treatment and preventionof conditions affected by 5-LO inhibition, further treatment options areneeded. The instant invention addresses that need by providing novel5-LO inhibitors which are useful for inhibiting leukotrienebiosynthesis.

SUMMARY OF THE INVENTION

The instant invention relates to compounds of Formula Ia which areleukotriene biosynthesis inhibitors, methods for their preparation, andmethods and pharmaceutical formulations for using these compounds inmammals, especially humans.

The compounds of Formula Ia are useful as pharmaceutical agents to slowor halt atherogenesis. Therefore, the instant invention provides amethod for treating atherosclerosis, which includes halting or slowingthe progression of atherosclerotic disease once it has become clinicallyevident, comprising administering a therapeutically effective amount ofa compound of Formula Ia to a patient in need of such treatment. Theinstant invention also provides methods for preventing or reducing therisk of developing atherosclerosis and atherosclerotic disease events,comprising administering a prophylactically effective amount of acompound of Formula Ia to a patient who is at risk of developingatherosclerosis or having an atherosclerotic disease event.

Additionally, the instant invention involves the use of compounds ofFormula Ia as anti-asthmatic, anti-allergic, anti-inflammatory andcytoprotective agents. They are also useful in treating angina, cerebralspasm, glomerular nephritis, hepatitis, endotoxemia, uveitis, andallograft rejection. The instant invention provides methods of treatmentcomprising administering a therapeutically effective amount of acompound of Formula Ia to a patient in need of the above-describedtreatments.

The instant invention further provides the use of a compound of FormulaIa in combination with other therapeutically effective agents.Additional embodiments will be evident from the following detaileddescription.

DETAILED DESCRIPTION OF THE INVENTION

The novel leukotriene biosynthesis inhibitors of the instant inventionare compounds of structural Formula Ia

and the pharmaceutically acceptable salts, esters and solvates thereofwherein:

is selected from a single and a double bond;

“A” is selected from the group consisting of

-   -   (a) a 5-membered aromatic ring containing (i) one or more carbon        atoms, (ii) one heteroatom selected from oxygen and sulfur,        and (iii) zero, one, two or three nitrogen atoms,    -   (b) a 5-membered aromatic ring containing one or more carbon        atoms and from one to four nitrogen atoms,    -   (c) a 6-membered aromatic ring containing carbon atoms and one,        two or three nitrogen atoms;    -   (d) a bicyclic aromatic ring system selected from benzothienyl,        indolyl, quinolinyl and naphthalenyl;    -   (e) phenyl, and    -   (f) —CH₂— phenyl;        and wherein A is optionally mono- or di-substituted with a        substituent independently selected at each occurrence from the        group consisting of (i) —F (ii) —Cl, (iii) —C₁₋₃alkyl optionally        substituted with one or more of halo for example including        —CF₃, (iv) —OC₁₋₃alkyl optionally substituted with one or more        of halo for example including —OCHF₂ and —OCF₃, (v)        —OC₃₋₆cycloalkyl, (vi) —CH₂OH, (vii) —COOR¹, (viii) —CN and (ix)        —NR¹⁰R¹¹;        X is selected from —O— and —S—;        Y is selected from:    -   (a) —NR⁶—CHR⁷ and —NR⁸—C(O)— wherein the nitrogen in Y is linked        to the 5-membered heterocyclic moiety of Formula Ia and the        carbon in Y is linked to the bicyclic heterocyclic moiety of        Formula Ia;    -   (b) —S—, —S(O)— and —S(O)₂—, and    -   (c) —O—;        R¹ is selected from the group consisting of —H, —C₁₋₆ alkyl and        —C₃₋₆ cycloalkyl;        R² is selected from the group consisting of —H, —OH, —F,        —C₁₋₃alkyl, —OC₁₋₃alkyl and —OC(O)—C₁₋₃alkyl;        R³ is selected from the group consisting of —H, —C₁₋₆alkyl,        —C₁₋₆alkyl substituted with one or more of fluoro including for        example but not limited to —C₁₋₆ perfluoroalkyl such as —CF₃ and        —CF₂CF₃, —C₁₋₆alkyl substituted with R⁹, —C₂₋₆alkenyl,        —C₃₋₆cycloalkyl, —C₅₋₇cycloalkenyl and -Z;        R⁴ is selected from the group consisting of —H, —C₁₋₆alkyl,        —C₁₋₆alkyl substituted with one or more of fluoro including for        example but not limited to —C₁₋₆ perfluoroalkyl such as —CF₃ and        —CF₂CF₃, —C₁₋₆alkyl substituted with R⁹, —C₂₋₆alkenyl,        —C₃₋₆cycloalkyl, —C₅₋₇cycloalkenyl and -Z;        or R³ and R⁴ together represent oxo;        or R³ and R⁴ are joined together with the carbon to which they        are attached to form a ring selected from the group consisting        of a —C₃₋₆cycloalkyl ring and a —C₅₋₇cycloalkenyl ring, provided        that when R³ and        R⁴ are joined together with the carbon to which they are        attached to form a —C₅₋₇cycloalkenyl ring, there is no double        bond at the C-1 position in the ring;        or R², R³ and R⁴ are joined together with the carbon to which        they are attached to form a cycloalkenyl ring selected from:

R⁵ is absent or is a substituent selected from the group consisting of—C₁₋₆ alkyl, —C₃₋₆ cycloalkyl and halo;R⁶ is selected from the group consisting of (a) —H, (b) —C₁₋₄ alkyl, (c)—C(O)C₁₋₄ alkyl, and (d) —C(O)phenyl optionally substituted with —C₁₋₄alkyl;R⁷ is selected from the group consisting of (a) —H, (b) —C₁₋₄ alkyl, (c)—C₃₋₆cycloalkyl, (d) phenyl optionally mono- or di-substituted with asubstituent independently selected at each occurrence from the groupconsisting of —C₁₋₄ alkyl, —F and —Cl, and (e) a 5-membered aromaticring containing (i) one or more carbon atoms, (ii) one heteroatomselected from oxygen and sulfur, and (iii) zero, one, two or threenitrogen atoms;R⁸ is selected from the group consisting of —H and —C₁₋₄ alkyl;R⁹ is selected from the group consisting of —COOR¹, —C(O)H, —CN,—CR¹R¹OH, —OR¹, —S—C₁₋₆alkyl and —S—C₃₋₆ cycloalkyl;R¹⁰ is selected from the group consisting of —H, —C₁₋₆ alkyl, —C₃₋₆cycloalkyl and —COOR¹;R¹¹ is selected from the group consisting of —H, —C₁₋₆ alkyl and —C₃₋₆cycloalkyl; andZ is selected from the group consisting of

-   -   (a) a 5-membered aromatic ring containing (i) one or more carbon        atoms, (ii) one heteroatom selected from oxygen and sulfur,        and (iii) zero, one, two or three nitrogen atoms,    -   (b) a 5-membered aromatic ring containing one or more carbon        atoms and from one to four nitrogen atoms,    -   (c) a 6-membered aromatic ring containing carbon atoms and one,        two or three nitrogen atoms;    -   (d) phenyl, and    -   (e) —CH₂— phenyl and —CH₂-dioxolanyl,        and wherein Z is optionally mono- or di-substituted with a        substituent independently selected at each occurrence from the        group consisting of (i) —F, (ii) —Cl, (iii) —C₁₋₃alkyl        optionally substituted with one or more of halo for example        including —CF₃, (iv) —OC₁₋₃alkyl optionally substituted with one        or more of halo, (v) —OC₃₋₆cycloalkyl, (vi) —CH₂OH, (vii)        —COOR¹, (viii) —CN and (ix) —NR¹⁰R¹¹.

In one embodiment of this invention are compounds within the scope ofFormula Ia having structural Formula Ib:

and the pharmaceutically acceptable salts, esters and solvates thereofwhereinR¹² is selected from the group consisting of —H and —F;R¹³ is absent or is a substituent at the 3- or 4-position and isselected from the group consisting of (i) —F, (ii) —Cl, (iii) —C₁₋₃alkyloptionally substituted with one or more of halo for example including—CF₃, (iv) —OC₁₋₃ alkyl optionally substituted with one or more of halofor example including —OCHF₂ and —OCF₃, (v) —OC₃₋₆cycloalkyl, (vi)—CH₂OH, (vii) —COOR¹, (viii) —CN and (ix) —NR¹⁰R¹¹; and the remainingvariables are as defined in Formula Ia. In a class of this embodiment,R¹³ is selected from the group consisting of —F, —OCF₃, —OCHF₂, —CN,—CH₃ and —OCH₃, and in a sub-class R¹³ is —F.

In another class of this embodiment are compounds within the scope ofFormula Ib having the following structural Formula I:

and the pharmaceutically acceptable salts, esters and solvates thereofwherein the variables present in Formula I are as defined in Formula Ib.

In another embodiment of this invention are compounds within the scopeof Formula Ia, having structural Formula Ic:

and the pharmaceutically acceptable salts, esters and solvates thereofwhereinY is selected from —S— and —O—;R¹² is selected from the group consisting of —H and —F;R¹³ is absent or is a substituent at the 3- or 4-position and isselected from the group consisting of (i) —F, (ii) —Cl, (iii) —C₁₋₃alkyloptionally substituted with one or more of halo for example including—CF₃, (iv) —OC₁₋₃alkyl optionally substituted with one or more of halofor example including —OCHF₂ and —OCF₃, (v) —OC₃₋₆cycloalkyl, (vi)—CH₂OH, (vii) —COOR¹, (viii) —CN and (ix) —NR¹⁰R¹¹; and the remainingvariables are as defined in Formula Ia. In a class of this embodiment,R¹³ is selected from the group consisting of —F, —OCF₃, —OCHF₂, —CN,—CH₃ and —OCH₃, and in a sub-class R¹³ is —F.

In another embodiment of this invention are compounds of Formula Iawherein A is selected from the group consisting of:

a) a 5-membered aromatic ring containing (i) one or more carbon atoms,(ii) one heteroatom selected from oxygen and sulfur, and (iii) zero,one, two or three nitrogen atoms,b) a 5-membered aromatic ring containing one or more carbon atoms andfrom one to four nitrogen atoms,c) a 6-membered aromatic ring containing carbon atoms and one, two orthree nitrogen atoms, andd) phenyl,and wherein A is unsubstituted, mono- or di-substituted as described inFormula Ia. In a class of this embodiment, A is unsubstituted, mono- ordi-substituted as described in Formula Ia, and is selected from thegroup consisting of thienyl, furanyl, oxazolyl, thiazolyl, tetrazolyl,pyridinyl and phenyl, and particularly thiazolyl, pyridinyl and phenyl.In a sub-class of this embodiment, A is selected from phenyl, optionallysubstituted at the 3- or 4-position with a substituent selected from —F,—OCF₃, —OCHF₂, —CN, —CH₃ and —OCH₃, and optionally substituted at the2-position with —F. More particularly, A is 4-fluoro-phenyl.

In another embodiment of this invention are compounds of Formula Ia, Ib,Ic and I wherein X is —S—. In another embodiment are compounds ofFormula Ia, Ib, Ic and I wherein X is —O—.

In another embodiment of this invention are compounds of Formula Iawherein Y is selected from —NR⁶—CHR⁷ and —NR⁸—C(O)—. In a class of thisembodiment Y is —NR⁶—CHR⁷—, and in a sub-class Y is —NR⁶—CH₂—. Inanother embodiment are compounds of Formula Ia wherein Y is selectedfrom —S— and —O—.

In another embodiment of this invention are compounds of Formula Iawherein “

” is a double bond.

In another embodiment of this invention are compounds of Formula Iawherein R¹ is selected from —H and —C₁₋₆ alkyl. In a class of thisembodiment, R¹ is selected from —H and —CH₃, and in a further sub-class,R¹ is —H.

In another embodiment of this invention are compounds of Formulas Ia,Ib, Ic and I wherein R² is selected from the group consisting of —H,—OH, —F, —C₁₋₃alkyl, —OCH₃, and —OC(O)CH₃. In a class of thisembodiment, R² is selected from —H and —OH, and more particularly it is—OH.

In another embodiment of this invention are compounds of Formulas Ia,Ib, Ic and I wherein R³ is selected from the group consisting of —H,—C₁₋₁₆alkyl, —C₁₋₆alkyl substituted with one or more of fluoro,—C₃₋₆cycloalkyl and phenyl. In a class of this embodiment, R³ isselected from —CH₃, —C₂H₅, —C₁₋₂alkyl substituted with fluoroparticularly —CF₃ and —CF₂CF₃, and cyclopropyl.

In another embodiment of this invention are compounds of Formulas Ia,Ib, Ic and I wherein R⁴ is selected from the group consisting of —H,—C₁₋₆alkyl, —C₁₋₆alkyl substituted with one or more of fluoro,—C₁₋₆alkyl substituted with R⁹, and —C₃₋₆cycloalkyl. In a class of thisembodiment, R⁴ is selected from —CH₃, —C₂H₅, —C₁₋₁₂alkyl substitutedwith fluoro particularly —CF₃ and —CF₂CF₃, cyclopropyl and—CH₂COOC₁₋₄alkyl.

In another embodiment of this invention are compounds of Formulas Ia,Ib, Ic and I wherein R³ and R⁴ together represent oxo, or R³ and R⁴together with the carbon to which they are attached represent a—C₃₋₆cycloalkyl ring.

In another embodiment of this invention are compounds of Formulas Ia, Iband Ic wherein R⁵ is selected from —H, —CH₃, —F and —Cl. In a class ofthis embodiment, R⁵ is selected from —H and —CH₃.

In another embodiment of this invention are compounds of Formulas Ia, Iband I wherein R⁶ is selected from the group consisting of —H, —CH₃ and—COCH₃. In a class of this embodiment, R⁶ is —H.

In another embodiment of this invention are compounds of Formulas Ia andIb wherein R⁷ is selected from the group consisting of —H and —C₁₋₄alkyl. In a subclass of this embodiment, R⁷ is —H.

In another embodiment of this invention are compounds of Formula Iawherein R⁸ is —H.

In another embodiment of this invention are compounds of Formulas Ia,Ib, Ic and I wherein R⁹ is —COOR¹, and particularly —COOC₁₋₆alkyl.

In another embodiment of this invention are compounds of Formulas Ia,Ib, Ic and I wherein R¹⁰ is selected from —H and —C₁₋₆ alkyl.

In another embodiment of this invention are compounds of Formulas Ia,Ib, Ic and I wherein R¹¹ is selected from —H and —C₁₋₆ alkyl.

In another embodiment of this invention are compounds of Formulas Ia,Ib, Ic and I wherein Z is unsubstituted, mono- or di-substituted asdescribed in Formula Ia and is selected from the group consisting ofphenyl, benzyl, pyridinyl, thiazolyl, dioxolanyl and tetrazolyl. In aclass of this embodiment, Z is unsubstituted, mono- or di-substitutedand is selected from the group consisting of phenyl, pyridinyl andthiazolyl.

Compounds of this invention include but are not limited to thefollowing:4-bromo-N-{[4-(4-fluorophenyl)-2-oxo-2H-chromen-7-yl]methyl}-N-{5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}benzamide;M+1=646 and 648; prepared according to methods A and B;4-(4-fluorophenyl)-7-{[{5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}(isopropyl)amino]methyl}-2H-chromen-2-one;M+1=506; prepared according to method A and D;7-[({5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-4-(2-methyl-1,3-thiazol-4-yl)-2H-chromen-2-one;M+1=467; prepared according to method C and A;4-(4-fluorophenyl)-7-[({5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-6-methyl-2H-chromen-2-one;M+1=478; prepared according to method C and A and B;N-{[4-(4-fluorophenyl)-2-oxo-2H-chromen-7-yl]methyl}-N-{5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}acetamide;M+1=506; prepared according to method B and A;4-(4-fluorophenyl)-7-({[5-(1-hydroxy-1-phenylethyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-2H-chromen-2-one;M+1=458; prepared according to method A and B;4-(4-fluorophenyl)-7-[({5-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one;M+1=504; prepared according to method A and B;4-(4-fluorophenyl)-7-[({5-[(1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one;M+1=450; prepared according to method A and B;4-(4-fluorophenyl)-7-{[{5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}(methyl)amino]methyl}-2H-chromen-2-one;M+1=478; prepared according to method A and B;4-(4-fluorophenyl)-7-[({5-[(1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one;M+1=450; prepared according to method A and B;3-{7-[({5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2-oxo-2H-chromen-4-yl}benzonitrile;M+1=471; prepared according to method A and B;4-(4-fluorophenyl)-7-({[5-(2,2,3,3,3-pentafluoro-1-hydroxy-1-methylpropyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-2H-chromen-2-one;M+1=500; prepared according to method A and B;4-(4-fluorophenyl)-7-({[5-(1-hydroxycyclopentyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-2H-chromen-2-one;M+1=422; prepared according to method A and B;(R)-6-fluoro-4-(4-fluorophenyl)-7-[({5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one;(M+1=464; (R)-isomer in DMSO-d₆: 8.57 (t, 1H), 7.68-7.63 (m, 2H), 7.53(d, 1H), 7.42 (apparent t, 2H), 7.26 (s, 1H), 7.18 (d, 1H), 6.53 (s, 1),4.55 (d, 2H), 2.15-2.05 (m, 1H), 2.01-1.94 (m, 1H), 0.91 (t, 3H);prepared according to method A and B and separation on CHIRAL PAK ADslow eluting;(S)-6-fluoro-4-(4-fluorophenyl)-7-[({5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one;M+1=464; (S)-isomer in acetone-d₆: 7.70-7.65 (m, 2H), 7.58-7.52 (m, 2H),7.39 (apparent t, 2H), 7.23 (d, 1H), 6.42 (s, 1H), 6.10 (br s, 1H), 4.73(d, 2H), 2.26-2.17 (m, 1H), 2.14-2.03 (m, 1H), 0.97 (t, 3H); preparedaccording to method A and B and separation on CHIRAL PAK AD fasteluting;6-chloro-4-(4-fluorophenyl)-7-[({5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one;M+1=498; prepared according to method A and B;6-fluoro-4-(4-fluorophenyl)-7-[({5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one;M+1=482 for the racemate; prepared according to method A and B;4-(4-fluorophenyl)-7-[({5-[hydroxy(phenyl)methyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one;M+1=444; prepared according to method A and B;7-({[5-(1-ethyl-1-hydroxypropyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-6-fluoro-4-(4-fluorophenyl)-2H-chromen-2-one;M+1=442; prepared according to method A and B;4-(4-fluorophenyl)-7-({[5-(1-hydroxy-1-methylpropyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-2H-chromen-2-one;M+1=410; prepared according to method A and B;7-({[5-(1-ethylpropyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-4-(4-fluorophenyl)-2H-chromen-2-one;M+1=408; prepared according to method A and B;4-[3-(difluoromethoxy)phenyl]-7-({[5-(1-ethyl-1-hydroxypropyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-2H-chromen-2-one;M+1=472; prepared according to method A and B;4-(4-fluorophenyl)-7-[({5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one;M+1=464 (racemic); prepared according to method A and B;(+)-4-(4-fluorophenyl)-7-[({5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one;M+1=464; prepared according to method A and B and separation on CHIRALPAK AD slow eluting, see example 7;(−)-4-(4-fluorophenyl)-7-[({5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one;M+1=464; prepared according to method A and B and separation on CHIRALPAK AD fast eluting, see example 7;7-({[5-(1-ethyl-1-hydroxypropyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-4-[3-(trifluoromethoxy)phenyl]-2H-chromen-2-one;M+1=490; prepared according to method A and B;6-chloro-7-({[5-(1-ethyl-1-hydroxypropyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-4-phenyl-2H-chromen-2-one;M+1=440; prepared according to method A and B;7-({[5-(1-ethyl-1-hydroxypropyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-4-(3-methylphenyl)-2H-chromen-2-one;M+1=420; prepared according to method C and B;7-(1-{[5-(1-ethyl-1-hydroxypropyl)-1,3,4-oxadiazol-2-yl]amino}ethyl)-4-(4-fluorophenyl)-2H-chromen-2-one;M+1=438; prepared according to method A and B;7-({[5-(1-ethyl-1-fluoropropyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-4-(4-fluorophenyl)-2H-chromen-2-one;M+1=426; prepared according to method A and B;7-{[(5-cyclobutyl-1,3,4-oxadiazol-2-yl)amino]methyl}-4-(4-fluorophenyl)-2H-chromen-2-one;M+1=392; prepared according to method A and B;7-{([(5-cyclopentyl-1,3,4-oxadiazol-2-yl)amino]methyl}-4-(4-fluorophenyl)-2H-chromen-2-one;M+1=406; prepared according to method A and B;7-({[5-(1-ethyl-1-hydroxypropyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-4-(4-fluorophenyl)chroman-2-one;M+1=426; prepared according to method A and B;7-{[[5-(1-ethyl-1-hydroxypropyl)-1,3,4-oxadiazol-2-yl](methyl)amino]methyl}-4-(4-fluorophenyl)-2H-chromen-2-one;M+1=438; prepared according to method A and B;7-({[5-(1-ethyl-1-hydroxypropyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-4-(3-fluorophenyl)-2H-chromen-2-one;M+1=424; prepared according to method A and B;4-(2,4-difluorophenyl)-7-({[5-(1-ethyl-1-hydroxypropyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-2H-chromen-2-one;M−1=440; prepared according to method A and B;7-({[5-(1-ethyl-1-hydroxypropyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-4-(3-methoxyphenyl)-2H-chromen-2-one;M+1=436; prepared according to method A and B;7-({[5-(1-ethyl-1-hydroxypropyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-4-(4-methoxyphenyl)-2H-chromen-2-one;M+1=436; prepared according to method A and B;7-({[5-(1-ethyl-1-hydroxypropyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-4-phenyl-2H-chromen-2-one;M+1=406; prepared according to method A and B;7-[({5-[dicyclopropyl(hydroxy)methyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-4-(4-fluorophenyl)-2H-chromen-2-one;M+1=448; prepared according to method A and B;7-({[5-(1-ethyl-1-hydroxypropyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-4-(4-fluorophenyl)-2H-chromen-2-one;M+1=424; prepared according to method A and B;N-[5-(1-ethyl-1-hydroxypropyl)-1,3,4-oxadiazol-2-yl]-N-{[4-(4-fluorophenyl)-2-oxo-2H-chromen-7-yl]methyl}acetamide;M+1=466; prepared according to method A;7-({[5-(1-ethyl-1-hydroxypropyl)-1,3,4-thiadiazol-2-yl]amino}methyl)-4-(4-fluorophenyl)-2H-chromen-2-one;M+1=440; prepared according to method B and D;7-{[(5-tert-butyl-1,3,4-thiadiazol-2-yl)amino]methyl}-4-(4-fluorophenyl)-2H-chromen-2-one;M−1=408; prepared according to method B;7-({5-[dicyclopropyl(hydroxy)methyl]-1,3,4-thiadiazol-2-yl}thio)-4-pyridin-3-yl-2H-chromen-2-one;M+1=450; prepared according to method C and E;7-({5-[dicyclopropyl(hydroxy)methyl]-1,3,4-thiadiazol-2-yl}thio)-4-(4-fluorophenyl)-2H-chromen-2-one;M+1=467; prepared according to method C and E;7-{[5-(1-ethyl-1-hydroxypropyl)-1,3,4-thiadiazol-2-yl]thio}-4-(4-fluorophenyl)-2H-chromen-2-one;M+1=443; prepared according to method C and E;

and the pharmaceutically acceptable salts, esters and solvates thereof,where appropriate.

The compounds of this invention, including compounds referenced as thoseof “Formula I,” “Formula Ia,” “Formula Ib,” “Formula Ic” or any othergeneric structural formulas used herein to describe the compounds ofthis invention, are intended to encompass compounds falling within thescope of each of these structural formulas including pharmaceuticallyacceptable salts, esters and solvates thereof where such salts, estersand solvates are possible. The term “pharmaceutically acceptable salts”refers to salts prepared from pharmaceutically acceptable non-toxicbases, such as for example, a sodium salt which could be prepared usingNaOH. Pharmaceutically acceptable esters of available hydroxy orcarboxylic acid groups can optionally be formed as well. Examples ofpharmaceutically acceptable esters include, but are not limited to,—C₁₋₄ alkyl and —C₁₋₄ alkyl substituted with phenyl-, dimethylamino- andacetylamino.

Some of the compounds described herein contain one or more asymmetric(chiral) centers and may thus exist as racemic mixtures and opticalisomers including enantio-enriched mixtures, single enantiomers,diastereomers and mixtures of diastereomers. The present invention ismeant to comprehend all such possible enantiomers and diastereomers aswell as their racemic and resolved, enantiomerically pure andsubstantially pure forms, and pharmaceutically acceptable salts thereof.Furthermore, some of the crystalline forms of compounds of the presentinvention may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, some of the compounds ofthe instant invention may form solvates with water or common organicsolvents. Such solvates and hydrates are likewise encompassed within thescope of this invention. Some of the compounds described herein containolefinic double bonds. The invention includes both E and Z geometricisomers.

Compounds of this invention may be separated into their individualdiastereoisomers by, e.g., fractional crystallization from suitablesolvents, e.g., methylene chloride/hexanes or EtOAc/hexanes, or viachiral chromatography using an optically active stationary phase.Absolute stereochemistry may be determined by X-ray crystallography ofcrystalline products or crystalline intermediates which are derivatized,if necessary, with a reagent containing a stereogenic center of knownconfiguration. Alternatively, any stereoisomer of a compound of thisinvention may be obtained by stereospecific synthesis using opticallypure starting materials or reagents of known absolute configuration.

As used herein “alkyl” is intended to include both branched- andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, e.g., methyl (Me), ethyl (Et),n-propyl (Pr), n-butyl (Bu), n-pentyl, n-hexyl, and the isomers thereofsuch as isopropyl (i-Pr), isobutyl (i-Bu), secbutyl (s-Bu), tertbutyl(t-Bu), isopentyl, isohexyl and the like. “Cycloalkyl” means amonocyclic saturated carbocyclic ring, having the specified number ofcarbon atoms, e.g., 3, 4, 5 or 6 carbon atoms. Examples of cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term “C₂₋₆alkenyl” as used herein, refers to a straight or branched2-6 carbon chain with at least one carbon-carbon double bond. Examplesof alkenyl include, but are not limited to, vinyl (—CH═CH₂), allyl,isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl,2-methyl-2-butenyl, and the like. The term “C₅₋₇ cycloalkenyl” as usedherein means a non-aromatic monocyclic ring having from 5 to 7 carbonatoms in the ring with at least one carbon-carbon double bond.

Within the definition of variables above, R³ and R⁴ can be joinedtogether with the carbon to which they are attached to form a—C₅₋₇cycloalkenyl ring wherein there is no double bond at the C-1position in the ring. The C-1 position is intended to be the ring carbonin the cycloalkenyl ring that is bonded to the core oxadiazolyl orthiadiazolyl ring in the generic structural formulas depicted herein. Inthis situation, C-1 is also bonded to R². This is illustrated belowusing the example where R³ and R⁴ are joined together with the carbon towhich they are attached to form a 3,4-cyclopentenyl ring, see (a):

The term “optionally substituted” means “unsubstituted or substituted,”and therefore, the generic structural formulas described hereinencompasses compounds containing the specified optional substituent aswell as compounds that do not contain the optional substituent. Forexample, the phrase “—C(O)phenyl optionally substituted with —C₁₋₄alkyl” encompasses unsubstituted —C(O)phenyl and —C(O)phenyl substitutedwith —C₁₋₄ alkyl. Each variable is independently defined each time itoccurs within the generic structural formula definitions. For example,when R⁹ is —CR¹R¹OH, R¹ is independently selected at each occurrence andeach R¹ can be the same or different.

Use of the term “substituted” is intended to encompass mono- andpoly-substitution on the specified moiety, unless otherwise specified. Amono-substituted moiety has one substituent, while a poly-substitutedmoiety has more than one substituent wherein each carbon atom, as wellas heteroatom such as nitrogen if present, that is available forsubstitution in the moiety may independently be unsubstituted, mono- orpoly-substituted and which results in the creation of a stablestructure. For example, “—C₁₋₆alkyl optionally substituted with fluoro”includes —CH₃, —CH₂F, —CHF₂ and —CF₃.

The terms “halo” or “halogen” are meant to include fluoro, chloro, bromoand iodo, unless otherwise noted. Fluoro and chloro are preferred, andfluoro is most preferred.

Examples of 5-membered aromatic rings within the definitions of A and Zinclude but are not limited to thienyl, furanyl, oxazolyl, thiazolyl,pyrrolyl, pyrazolyl, imidazolyl, and tetrazolyl, represented by thestructural formulas below:

Examples of 6-membered aromatic rings comprised of carbon and one, twoor three of —N— within the definition of A and Z include but are notlimited to pyridinyl, pyrimidinyl, pyrazinyl and triazinyl representedby the structural formulas below:

The ability of the compounds of this invention to inhibit biosynthesisof the leukotrienes makes them useful for preventing or reversing thesymptoms induced by the leukotrienes in a human subject. This inhibitionof the mammalian biosynthesis of leukotrienes indicates that thecompounds and pharmaceutical compositions thereof are useful to treat,prevent, or ameliorate atherosclerosis in mammals, and especially inhumans. Therefore, the compounds of this invention can be used for thetreatment of atherosclerosis comprising administering a therapeuticallyeffective amount of a compound of this invention to a patient in need ofsuch treatment. A further aspect of this invention involves a method forpreventing or reducing the risk of developing atherosclerosis,comprising administering a prophylactically effective amount of acompound of this invention to a patient in need of such treatment.Atherosclerosis is characterized by the deposition of atheromatousplaques containing cholesterol and lipids on the innermost layer of thewalls of large and medium-sized arteries. Atherosclerosis encompassesvascular diseases and conditions that are recognized and understood byphysicians practicing in the relevant fields of medicine.Atherosclerotic cardiovascular disease including restenosis followingrevascularization procedures, coronary heart disease (also known ascoronary artery disease or ischemic heart disease), cerebrovasculardisease including multi-infarct dementia, and peripheral vessel diseaseincluding erectile dysfunction, are all clinical manifestations ofatherosclerosis and are therefore encompassed by the terms“atherosclerosis” and “atherosclerotic disease.”

A compound of the instant invention may be administered to prevent orreduce the risk of occurrence, or recurrence where the potential exists,of a coronary heart disease (CHD) event, a cerebrovascular event, and/orintermittent claudication. Coronary heart disease events are intended toinclude CHD death, myocardial infarction (i.e., a heart attack), andcoronary revascularization procedures. Cerebrovascular events areintended to include ischemic or hemorrhagic stroke (also known ascerebrovascular accidents) and transient ischemic attacks. Intermittentclaudication is a clinical manifestation of peripheral vessel disease.The term “atherosclerotic disease event” as used herein is intended toencompass coronary heart disease events, cerebrovascular events, andintermittent claudication. It is intended that persons who havepreviously experienced one or more non-fatal atherosclerotic diseaseevents are those for whom the potential for recurrence of such an eventexists.

Accordingly, the instant invention also provides a method for preventingor reducing the risk of a first or subsequent occurrence of anatherosclerotic disease event comprising the administration of aprophylactically effective amount of a compound of this invention to apatient at risk for such an event. The patient may already haveatherosclerotic disease at the time of administration, or may be at riskfor developing it.

The method of this invention serves to prevent or slow newatherosclerotic lesion or plaque formation, and to prevent or slowprogression of existing lesions or plaques, as well as to causeregression of existing lesions or plaques. Accordingly, one aspect ofthis invention involves a method for halting or slowing the progressionof atherosclerosis, including halting or slowing atherosclerotic plaqueprogression, comprising administering a therapeutically effective amountof a compound of this invention to a patient in need of such treatment.This method also includes halting or slowing progression ofatherosclerotic plaques existing at the time the instant treatment isbegun (i.e., “existing atherosclerotic plaques”), as well as halting orslowing formation of new atherosclerotic plaques in patients withatherosclerosis.

Another aspect of this invention involves a method for regression ofatherosclerosis, including regression of atherosclerotic plaquesexisting at the time the instant treatment is begun, comprisingadministering a therapeutically effective amount of a compound of thisinvention to a patient in need of such treatment.

Another aspect of this invention involves a method for preventing orreducing the risk of atherosclerotic plaque rupture comprisingadministering a prophylactically effective amount of a compound of thisinvention to a patient in need of such treatment. Another aspect of thisinvention involves a method for treating, preventing, or amelioratingangina and/or myocardial ischemia, comprising administering atherapeutically or prophylactically effective amount, as appropriate, ofa compound of this invention to a patient in need of such treatment.

Additionally, the activity of the instant compounds as leukotrienebiosynthesis inhibitors makes them useful for treating, preventing, orameliorating: 1) pulmonary disorders including diseases such as asthma,chronic bronchitis, and related obstructive airway diseases, 2)allergies and allergic reactions such as allergic rhinitis, contactdermatitis, allergic conjunctivitis, and the like, 3) inflammation suchas arthritis or inflammatory bowel disease, 4) pain, 5) skin disorderssuch as atopic eczema, and the like, 6) cardiovascular disorders suchhypertension, platelet aggregation and the like, 7) renal insufficiencyarising from ischaemia induced by immunological or chemical(cyclosporin) etiology and 8) migraine or cluster headache, 9) ocularconditions such as uveitis, 10) hepatitis resulting from chemical,immunological or infectious stimuli, 11) trauma or shock states such asburn injuries, endotoxemia and the like, 12) allograft rejection, 13)prevention of side effects associated with therapeutic administration ofcytokines such as Interleukin II and tumor necrosis factor, 14) chroniclung diseases such as cystic fibrosis, bronchitis and other small- andlarge-airway diseases, 15) cholecystitis, 16) multiple sclerosis, 17)proliferation of myoblastic leukemia cells and 18) acne.

Thus, the compounds of the present invention may also be used to treator prevent mammalian (especially, human) disease states such as erosivegastritis; erosive esophagitis; diarrhea; cerebral spasm; prematurelabor; spontaneous abortion; dysmenorrhea; ischemia; noxiousagent-induced damage or necrosis of hepatic, pancreatic, renal, ormyocardial tissue; liver parenchymal damage caused by hepatoxic agentssuch as CCl₄ and D-galactosamine; ischemic renal failure;disease-induced hepatic damage; bile salt induced pancreatic or gastricdamage; trauma- or stress-induced cell damage; and glycerol-inducedrenal failure. Leukotriene biosynthesis inhibitors also act asinhibitors of tumor metastasis and exhibit cytoprotective action.

The cytoprotective activity of a compound may be observed in bothanimals and man by noting the increased resistance of thegastrointestinal mucosa to the noxious effects of strong irritants, forexample, the ulcerogenic effects of aspirin or indomethacin. In additionto lessening the effect of non-steroidal anti-inflammatory drugs on thegastrointestinal tract, animal studies show that cytoprotectivecompounds will prevent gastric lesions induced by oral administration ofstrong acids, strong bases, ethanol, hypertonic saline solutions, andthe like. Two assays can be used to measure cytoprotective ability.These assays are: (A) an ethanol-induced lesion assay and (B) anindomethacin-induced ulcer assay and are described in EP 140,684. Inparticular, the compounds of the invention would be useful to reduce thegastric erosion caused by co-administration of a cyclooxygenase-2selective inhibitor such as rofecoxib (VIOXX®), etoricoxib (ARCOXIA™),celecoxib (CELEBREX®) and valdecoxib (BEXTRA™), and low-dose aspirin.

In addition, the compounds of this invention can also be used for thetreatment of chronic obstructive pulmonary disease (COPD). As describedin S. Kilfeather, Chest, 2002, vol 121, 197, airway neutrophilia in COPDpatients is believed to be a contributing source of inflammation and isassociated with airway remodeling. The presence of neutrophils ismediated in part by LTB₄, and treatment with the instant compounds couldbe used to reduce neutrophilic inflammation in patients with COPD.

Furthermore, the compounds of this invention could be used for thetreatment of Alzheimer's disease; see Manev, H. and Manev, R.,“5-Lipoxygenase (ALOX5) and FLAP (ALOX5AP) gene polymorphisms as factorsin vascular pathology and Alzheimer's disease,” Medical Hypotheses(2006) 66, p. 501-503.

The term “patient” includes mammals, especially humans, who use theinstant active agents for the prevention or treatment of a medicalcondition. Administering of the drug to the patient includes bothself-administration and administration to the patient by another person.The patient may be in need of treatment for an existing disease ormedical condition, or may desire prophylactic treatment to prevent orreduce the risk for diseases and medical conditions affected byinhibition of leukotriene biosynthesis.

The term “therapeutically effective amount” is intended to mean thatamount of a drug or pharmaceutical agent that will elicit the biologicalor medical response of a tissue, a system, animal or human that is beingsought by a researcher, veterinarian, medical doctor or other clinician.The term “prophylactically effective amount” is intended to mean thatamount of a pharmaceutical drug that will prevent or reduce the risk ofoccurrence of the biological or medical event that is sought to beprevented in a tissue, a system, animal or human by a researcher,veterinarian, medical doctor or other clinician.

The magnitude of prophylactic or therapeutic dose of a compound of thisinvention will, of course, vary with the nature of the severity of thecondition to be treated and with the particular compound and its routeof administration. It will also vary according to the age, weight andresponse of the individual patient. In general, the daily dose range foranti-asthmatic, anti-inflammatory, anti-allergic or anti-atheroscleroticuse and generally, uses other than cytoprotection, lie within the rangeof from about 0.001 mg to about 100 mg per kg body weight of a mammal,preferably 0.01 mg to about 10 mg per kg, and most preferably 0.1 to 1mg per kg, in single or divided doses. On the other hand, it may benecessary to use dosages outside these limits in some cases. Asexamples, the total daily dosage amount may be selected from, but notlimited to, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100mg, 125 mg, 150 mg, 200 mg and 250 mg in single or divided daily doses.

In the case where an oral composition is employed, a suitable dosagerange for anti-asthmatic, anti-inflammatory, anti-allergic oranti-atherosclerotic use is, e.g., from about 0.01 mg to about 100 mg ofa compound of this invention per kg of body weight per day, preferablyfrom about 0.1 mg to about 10 mg per kg and for cytoprotective use from0.1 mg to about 100 mg (preferably from about 1 mg to about 100 mg andmore preferably from about 10 mg to about 100 mg) of a compound of thisinvention per kg of body weight per day.

For use where a composition for intravenous administration is employed,a suitable dosage range for anti-asthmatic, anti-inflammatory,anti-atherosclerotic or anti-allergic use is from about 0.001 mg toabout 25 mg (preferably from 0.01 mg to about 1 mg) of a compound ofthis invention per kg of body weight per day and for cytoprotective usefrom about 0.1 mg to about 100 mg (preferably from about 1 mg to about100 mg and more preferably from about 1 mg to about 10 mg) of a compoundof this invention per kg of body weight per day.

For the treatment of diseases of the eye, ophthalmic preparations forocular administration comprising 0.001-1% by weight solutions orsuspensions of the compounds of this invention in an acceptableophthalmic formulation may be used.

The exact amount of a compound of this invention to be used as acytoprotective agent will depend on, inter alia, whether it is beingadministered to heal damaged cells or to avoid future damage, on thenature of the damaged cells (e.g., gastrointestinal ulcerations vs.nephrotic necrosis), and on the nature of the causative agent. Anexample of the use of a compound of this invention in avoiding futuredamage would be co-administration of a compound of this invention withan NSAID that might otherwise cause such damage (for example,indomethacin). For such use, the compound of this invention isadministered from 30 minutes prior up to 30 minutes after administrationof the NSAID. Preferably it is administered prior to or simultaneouslywith the NSAID, (for example, in a combination dosage form).

The pharmaceutical compositions of the present invention comprise acompound of this invention as an active ingredient and apharmaceutically acceptable carrier and optionally other therapeuticingredients. Any suitable route of administration may be employed forproviding a mammal, especially a human with an effective dosage of acompound of the present invention. For example, oral, rectal, topical,parenteral, ocular, pulmonary, nasal, and the like may be employed.Dosage forms include tablets, troches, dispersions, suspensions,solutions, capsules, creams, ointments, aerosols, and the like. For usein treating or preventing atherosclerosis and related disease events,oral formulation is preferred.

The compositions include compositions suitable for oral, rectal,topical, parenteral (including subcutaneous, intramuscular, andintravenous), ocular (ophthalmic), pulmonary (nasal or buccalinhalation), or nasal administration, although the most suitable routein any given case will depend on the nature and severity of theconditions being treated and on the nature of the active ingredient.They may be conveniently presented in unit dosage form and prepared byany of the methods well-known in the art of pharmacy.

For administration by inhalation, the compounds of the present inventionare conveniently delivered in the form of an aerosol spray presentationfrom pressurized packs or nebulisers. The compounds may also bedelivered as powders which may be formulated and the powder compositionmay be inhaled with the aid of an insufflation powder inhaler device.The preferred delivery system for inhalation is a metered doseinhalation (MDI) aerosol, which may be formulated as a suspension orsolution of a compound of this invention in suitable propellants, suchas fluorocarbons or hydrocarbons.

Suitable topical formulations of a compound of this invention includetransdermal devices, aerosols, creams, ointments, lotions, dustingpowders, and the like.

In practical use, the compounds of this invention can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). In preparing the compositions for oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like in the case of oral liquidpreparations, such as, for example, suspensions, elixirs and solutions;or carriers such as starches, sugars, microcrystalline cellulose,diluents, granulating agents, lubricants, binders, disintegrating agentsand the like in the case of oral solid preparations such as, forexample, powders, capsules and tablets, with the solid oral preparationsbeing preferred over the liquid preparations. Because of their ease ofadministration, tablets and capsules represent the most advantageousoral dosage unit form in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be coated by standardaqueous or nonaqueous techniques.

In addition to the common dosage forms set out above, the compounds ofthis invention may also be administered by controlled release meansand/or delivery devices such as those described in U.S. Pat. Nos.3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200; 4,008,719; and5,366,738 the disclosures of which are hereby incorporated herein byreference.

Pharmaceutical compositions of the present invention suitable for oraladministration may be presented as discrete units such as capsules,cachets or tablets, each containing a predetermined amount of the activeingredient, as a powder or granules or as a solution or a suspension inan aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or awater-in-oil liquid emulsion. Such compositions may be prepared by anyof the methods of pharmacy but all methods include the step of bringinginto association the active ingredient with the carrier whichconstitutes one or more necessary ingredients. In general, thecompositions are prepared by uniformly and intimately admixing theactive ingredient with liquid carriers or finely divided solid carriersor both, and then, if necessary, shaping the product into the desiredpresentation. For example, a tablet may be prepared by compression ormolding, optionally with one or more accessory ingredients. Compressedtablets may be prepared by compressing in a suitable machine, the activeingredient in a free-flowing form such as powder or granules, optionallymixed with a binder, lubricant, inert diluent, surface active ordispersing agent. Molded tablets may be made by molding in a suitablemachine, a mixture of the powdered compound moistened with an inertliquid diluent. Desirably, each tablet, cachet or capsule contains fromabout 1 mg to about 500 mg of the active ingredient. The following areexamples of representative pharmaceutical dosage forms for the compoundsof this invention:

Injectable Suspension (I.M.) mg/ml Compound of Formula Ia 10Methylcellulose 5.0 Tween 80 0.5 Benzyl alcohol 9.0 Benzalkoniumchloride 1.0 Water for injection to a total volume of 1 ml Tabletmg/tablet Compound of Formula Ia 25 Microcrystalline Cellulose 415Providone 14.0 Pregelatinized Starch 43.5 Magnesium Stearate 2.5 500Capsule mg/capsule Compound of Formula Ia 25 Lactose Powder 573.5Magnesium Stearate 1.5 600 Aerosol Per canister Compound of Formula Ia24 mg Lecithin, NF Liquid Concentrate 1.2 mg Trichlorofluoromethane, NF4.025 gm Dichlorodifluoromethane, NF 12.15 gm

The instant invention also encompasses a process for preparing apharmaceutical composition comprising combining a compound of thisinvention with a pharmaceutically acceptable carrier. Also encompassedis the pharmaceutical composition which is made by combining a compoundof this invention with a pharmaceutically acceptable carrier.

A therapeutically effective amount of a compound of this invention canbe used for the preparation of a medicament useful for treating orpreventing any of the medical conditions described herein, in dosageamounts described herein. For example, a compound of this invention canbe used for the preparation of a medicament useful for the treatment ofasthma, allergies and allergic conditions, inflammation, COPD or erosivegastritis. Additionally, the medicament may be useful for preventing orreducing the risk of developing atherosclerotic disease, halting orslowing the progression of atherosclerotic disease once it has becomeclinically manifest, and preventing or reducing the risk of a first orsubsequent occurrence of an atherosclerotic disease event. Themedicament comprised of a compound of this invention may also beprepared with one or more additional active agents, such as thosedescribed below.

One or more additional active agents may be used in combination with thecompounds of this invention in a single dosage formulation, or theactive agents of the combination may be administered to the patient inseparate dosage formulations, which allows for concurrent or sequentialadministration of the active agents.

In addition to the compounds of this invention, the pharmaceuticalcompositions of the present invention can also contain other activeagents (i.e., ingredients), such as cyclooxygenase inhibitors,non-steroidal anti-inflammatory drugs (NSAIDs), peripheral analgesicagents such as zomepirac diflunisal and the like. The weight ratio ofthe compound of this invention to the second active ingredient may bevaried and will depend upon the effective dose of each ingredient.Generally, an effective dose of each will be used. Thus, for example,when a compound of this invention is combined with an NSAID the weightratio of the compound of said compound to the NSAID will generally rangefrom about 1000:1 to about 1:1000, preferably about 200:1 to about1:200. Combinations of a compound of this invention and other activeingredients will generally also be within the aforementioned range, butin each case, an effective dose of each active ingredient should beused.

NSAIDs can be characterized into five groups: (1) propionic acidderivatives; (2) acetic acid derivatives; (3) fenamic acid derivatives;(4) oxicams; and (5) biphenylcarboxylic acid derivatives; or apharmaceutically acceptable salt thereof.

The propionic acid derivatives which may be used comprise: alminoprofen,benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen,flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen,oxaprozin, pirprofen, prano-profen, suprofen, tiaprofenic acid, andtioxaprofen. Structurally related propionic acid derivatives havingsimilar analgesic and anti-inflammatory properties are also intended tobe included in this group. Thus, “propionic acid derivatives” as definedherein are non-narcotic analgesics/non-steroidal anti-inflammatory drugshaving a free —CH(CH₃)COOH or —CH₂CH₂COOH group (which optionally can bein the form of a pharmaceutically acceptable salt group, e.g.,—CH(CH₃)COO_Na⁺ or —CH₂CH₂COO_Na⁺), typically attached directly or via acarbonyl function to a ring system, preferably to an aromatic ringsystem.

The acetic acid derivatives which may be used comprise: indomethacin,which is a preferred NSAID, acemetacin, alclofenac, clidanac,diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac,isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, andzomepirac. Structurally related acetic acid derivatives having similaranalgesic and anti-inflammatory properties are also intended to beencompassed by this group. Thus, “acetic acid derivatives” as definedherein are non-narcotic analgesics/non-steroidal anti-inflammatory drugshaving a free —CH₂COOH group (which optionally can be in the form of apharmaceutically acceptable salt group, e.g., —CH₂COO⁻Na⁺), typicallyattached directly to a ring system, preferably to an aromatic orheteroaromatic ring system.

The fenamic acid derivatives which may be used comprise: flufenamicacid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamicacid. Structurally related fenamic acid derivatives having similaranalgesic and anti-inflammatory properties are also intended to beencompassed by this group. Thus, “fenamic acid derivatives” as definedherein are non-narcotic analgesics/non-steroidal anti-inflammatory drugswhich contain the basic structure:

which can bear a variety of substituents and in which the free —COOHgroup can be in the form of a pharmaceutically acceptable salt group,e.g., —COO⁻Na⁺.

The biphenylcarboxylic acid derivatives which can be used comprise:diflunisal and flufenisal. Structurally related biphenyl-carboxylic acidderivatives having similar analgesic and anti-inflammatory propertiesare also intended to be encompassed by this group. Thus,“biphenylcarboxylic acid derivatives” as defined herein are non-narcoticanalgesics/non-steroidal anti-inflammatory drugs which contain the basicstructure:

which can bear a variety of substituents and in which the free —COOHgroup can be in the form of a pharmaceutically acceptable salt group,e.g., —COO⁻Na⁺.

The oxicams which can be used in the present invention comprise:isoxicam, piroxicam, sudoxicam and tenoxican. Structurally relatedoxicams having similar analgesic and anti-inflammatory properties arealso intended to be encompassed by this group. Thus, “oxicams” asdefined herein are non-narcotic analgesics/non-steroidalanti-inflammatory drugs which have the general formula:

wherein R is an aryl or heteroaryl ring system.

The following NSAIDs may also be used: amfenac sodium, aminoprofen,anitrazafen, antrafenine, auranofin, bendazac lysinate, benzydanine,beprozin, broperamole, bufezolac, cinmetacin, ciproquazone, cloximate,dazidamine, deboxamet, delmetacin, detomidine, dexindoprofen, diacerein,di-fisalamine, difenpyramide, emorfazone, enfenamic acid, enolicam,epirizole, etersalate, etodolac, etofenamate, fanetizole mesylate,fenclorac, fendosal, fenflumizole, feprazone, floctafenine, flunixin,flunoxaprofen, fluproquazone, fopirtoline, fosfosal, furcloprofen,glucametacin, guaimesal, ibuproxam, isofezolac, isonixim, isoprofen,isoxicam, lefetamine HCl, leflunomide, lofemizole, lonazolac calcium,lotifazole, loxoprofen, lysin clonixinate, meclofenamate sodium,meseclazone, nabumetone, nictindole, nimesulide, orpanoxin, oxametacin,oxapadol, perisoxal citrate, pimeprofen, pimetacin, piproxen, pirazolac,pirfenidone, proglumetacin maleate, proquazone, pyridoxiprofen,sudoxicam, talmetacin, talniflumate, tenoxicam, thiazolinobutazone,thielavin B, tiaramide HCl, tiflamizole, timegadine, tolpadol,tryptamid, and ufenamate. The following NSAIDs, designated by companycode number (see e.g., Pharmaprojects), may also be used: 480156S,AA861, AD1590, AFP802, AFP860, AI77B, AP504, AU8001, BPPC, BW540C,CHINOIN 127, CN100, EB382, EL508, F1044, GV3658, ITF182, KCNTEI6090,KME4, LA2851, MR714, MR897, MY309, ONO3144, PR823, PV102, PV108, R830,RS2131, SCR152, SH440, SIR133, SPAS510, SQ27239, ST281, SY6001, TA60,TAI-901 (4-benzoyl-1-indancarboxylic acid), TVX2706, U60257, UR2301, andWY41770.

Finally, NSAIDs which may also be used include the salicylates,specifically acetyl salicylic acid and the phenylbutazones, andpharmaceutically acceptable salts thereof.

In addition to indomethacin, other preferred NSAIDs are acetyl salicylicacid, diclofenac, fenbufen, fenoprofen, flurbiprofen, ibuprofen,ketoprofen, naproxen, phenylbutazone, piroxicam, sulindac, and tolmetin.Pharmaceutical compositions comprising compounds of this invention mayalso contain inhibitors of the biosynthesis of the leukotrienes such asare disclosed in EP 138,481 (Apr. 24, 1985), EP 115,394 (Aug. 8, 1984),EP 136,893 (Apr. 10, 1985), and EP 140,709 (May 8, 1985), which arehereby incorporated herein by reference.

The compounds of this invention may also be used in combination withleukotriene antagonists such as those disclosed in EP 106,565 (Apr. 25,1984) and EP 104,885 (Apr. 4, 1984) which are hereby incorporated hereinby reference and others known in the art such as those disclosed in EPApplication Nos. 56,172 (Jul. 21, 1982) and 61,800 (Jun. 10, 1982); andin U.K. Patent Specification No. 2,058,785 (Apr. 15, 1981), which arehereby incorporated herein by reference.

Pharmaceutical compositions comprising compounds of this invention mayalso contain as the second active ingredient, prostaglandin antagonistssuch as those disclosed in EP 11,067 (May 28, 1980) or thromboxaneantagonists such as those disclosed in U.S. Pat. No. 4,237,160. They mayalso contain histidine decarboxylase inhibitors such asα-fluoromethylhistidine, described in U.S. Pat. No. 4,325,961. Thecompounds of this invention may also be advantageously combined with anH₁ or H₂-receptor antagonist, such as for instance acetamazole,aminothiadiazoles disclosed in EP 40,696 (Dec. 2, 1981), benadryl,cimetidine, famotidine, framamine, histadyl, phenergan, ranitidine,terfenadine and like compounds, such as those disclosed in U.S. Pat.Nos. 4,283,408; 4,362,736; and 4,394,508. The pharmaceuticalcompositions may also contain a K⁺/H⁺ ATPase inhibitor such asomeprazole, disclosed in U.S. Pat. No. 4,255,431, and the like.Compounds of this invention may also be usefully combined with most cellstabilizing agents, such as1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane and related compoundsdescribed in British Patent Specifications 1,144,905 and 1,144,906.Another useful pharmaceutical composition comprises compounds of thisinvention in combination with serotonin antagonists such asmethysergide, the serotonin antagonists described in Nature, 316,126-131 (1985), and the like. Each of the references referred to in thisparagraph is hereby incorporated herein by reference.

Other advantageous pharmaceutical compositions comprise the compounds ofthis invention in combination with anti-cholinergics such as ipratropiumbromide, bronchodilators such as the beta agonist salbutamol,metaproterenol, terbutaline, fenoterol and the like, and theanti-asthmatic drugs theophylline, choline theophyllinate andenprofylline, the calcium antagonists nifedipine, diltiazem,nitrendipine, verapamil, nimodipine, felodipine, etc., and thecorticosteroids, hydrocortisone, methylprednisolone, betamethasone,dexamethasone, beclomethasone, and the like.

Furthermore, additional active agents such as anti-atheroscleroticagents may be used in combination with the compounds of this invention.The additional active agent or agents can be lipid altering compoundssuch as HMG-CoA reductase inhibitors, or agents having otherpharmaceutical activities, or agents that have both lipid-alteringeffects and other pharmaceutical activities. Examples of HMG-CoAreductase inhibitors useful for this purpose include statins in theirlactonized or dihydroxy open acid forms and pharmaceutically acceptablesalts and esters thereof, including but not limited to lovastatin(MEVACOR®; see U.S. Pat. No. 4,342,767); simvastatin (ZOCOR®; see U.S.Pat. No. 4,444,784); dihydroxy open-acid simvastatin, particularly theammonium or calcium salts thereof; pravastatin, particularly the sodiumsalt thereof (PRAVACHOL®; see U.S. Pat. No. 4,346,227); fluvastatinparticularly the sodium salt thereof (LESCOL®; see U.S. Pat. No.5,354,772); atorvastatin, particularly the calcium salt thereof(LIPITOR®; see U.S. Pat. No. 5,273,995); nisvastatin also referred to asNK-104 (see PCT international publication number WO 97/23200); androsuvastatin (CRESTOR®; see U.S. Pat. No. 5,260,440). Additional activeagents which may be employed in combination with a compound of thisinvention include but are not limited to HMG-CoA synthase inhibitors;cholesterol absorption inhibitors such as ezetimibe (ZETIA®) which is1-(4-fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl)]-4(S)-(4-hydroxyphenyl)-2-azetidinone,described in U.S. Pat. Nos. Re. 37721 and 5,846,966; cholesterol estertransfer protein (CETP) inhibitors, for example JTT-705 (Japan TobaccoCompany) and torcetrapib (Pfizer); squalene epoxidase inhibitors;squalene synthetase inhibitors (also known as squalene synthaseinhibitors); acyl-coenzyme A: cholesterol acyltransferase (ACAT)inhibitors including selective inhibitors of ACAT-1 or ACAT-2 as well asdual inhibitors of ACAT1 and -2; microsomal triglyceride transferprotein (MTP) inhibitors; probucol; niacin; bile acid sequestrants; LDL(low density lipoprotein) receptor inducers; platelet aggregationinhibitors, for example glycoprotein IIb/IIIa fibrinogen receptorantagonists and aspirin; human peroxisome proliferator activatedreceptor gamma (PPARγ) agonists including the compounds commonlyreferred to as glitazones for example troglitazone, pioglitazone androsiglitazone and, including those compounds included within thestructural class known as thiazolidinediones as well as those PPARγagonists outside the thiazolidinedione structural class; PPARα agonistssuch as clofibrate, fenofibrate including micronized fenofibrate, andgemfibrozil; PPAR dual α/γ agonists such as muraglitazar; vitamin B₆(also known as pyridoxine) and the pharmaceutically acceptable saltsthereof such as the HCl salt; vitamin B₁₂ (also known ascyanocobalamin); folic acid or a pharmaceutically acceptable salt orester thereof such as the sodium salt and the methylglucamine salt;anti-oxidant vitamins such as vitamin C and E and beta carotene;beta-blockers; angiotensin II antagonists such as losartan; angiotensinconverting enzyme inhibitors such as enalapril and captopril; calciumchannel blockers such as nifedipine and diltiazam; endothelianantagonists; agents that enhance ABC1 gene expression; FXR and LXRligands including both inhibitors and agonists; bisphosphonate compoundssuch as alendronate sodium; and cyclooxygenase-2 inhibitors such asrofecoxib and celecoxib.

Compounds of this invention can be tested using the following assays todetermine their mammalian leukotriene biosynthesis inhibiting activity.Representative tested compounds of this invention were shown to beinhibitors of leukotriene biosynthesis, with most having an IC₅₀ lessthan or equal to 4 μM in the Human 5-Lipoxygenase Enzyme Assay,described below, with preferred compounds tested in this assay having anIC₅₀ less than or equal to 0.100 μM. The representative tested compoundswere also shown to have activity as 5-LO inhibitors in the5-Lipoxygenase Human Whole Blood Assay, described below, with mosthaving an IC₅₀ less than or equal to 4 μM, and preferred compoundshaving an IC₅₀ of less than or equal to 0.500 μM.

Human 5-Lipoxygenase Enzyme Assay

The activity of 5-lipoxygenase was measured using a spectrophotometricassay and recombinant human 5-lipoxygenase as a source of enzyme. Human5-lipoxygenase was purified from Sf9 cells infected with the recombinantbaculovirus rvH5LO (8-1) containing the coding sequence for human5-lipoxygenase as described by Percival et al., (Eur. J. Biochem 210,109-117, 1992). The enzymatic activity was measured using aspectrophotometric assay from the optimal rate of conjugated dieneformation (absorbance at 238 nm) using the procedure described inRiendeau et al. (Biochem. Pharmacol. 38, 2313-2321, 1989) with minormodifications. The incubation mixture contained 25 mM potassiumphosphate, pH 7.5, 0.1 mM EDTA, 0.3 mM CaCl₂, 24 μg/mlphosphatidylcholine, 0.1 mM ATP, 0.5 mM DTT, 20 μM arachidonic acid (2μl from a 100-fold solution in ethanol), inhibitor (2 μl aliquot from a100-fold solution in DMSO) and an aliquot of purified 5-lipoxygenase.Reactions were initiated by the addition of the purified 5-lipoxygenaseand the rate of conjugated diene production was followed for 5 minutesat room temperature. The reaction was performed in a Costar UV plate(Cat. # 3635) and the absorbance changes at 238 nm were recorded with aMolecular Devices UV/VIS 96 well spectrophotometer (Spectra Max 190)using SOFTmax PRO software. Enzymatic activity was calculated from theoptimal rate of the reaction by a linear fit of the increase inabsorbance at 238 nm over 36 seconds. When the rate of diene formationis low (<0.01 Absorbance Unit/min) the linear fit is performed over 180seconds. The results are expressed as percentage of inhibition of thereaction rate relative to controls (typically between 0.001-0.005Absorbance Unit/min) containing the DMSO vehicle.

5-Lipoxygenase Human Whole Blood Assay

Fresh blood was collected in heparinized tubes by venipuncture fromconsenting volunteers. These volunteers have no apparent inflammatoryconditions and have not taken any nonsteroidal anti-inflammatory drugsfor at least 4 days prior to blood collection. Plasma was separated fromthe blood of each individual volunteer by centrifuging approximately 10mls of blood. A 50 mM stock solution of the calcium ionophore A23187(Sigma, St Louis, Mo., USA) in DMSO was diluted 40 fold with eachvolunteer's plasma to obtain a 1.25 mM working solution. A 250 μlaliquot of each blood was pre-incubated with either 0.5 μl of vehicle(DMSO) or test compounds in DMSO at 37° C. for 15 minutes. This wasfollowed with the addition of 5 μl of either plasma or the 1.25 mMworking solution (for each experiment, the blood and plasma was from thesame volunteer) resulting in a final concentration of 25 μM of A23187.The blood mixture was incubated at 37° C. for 30 minutes thencentrifuged at 1500 g at 4° C. for 10 minutes. The supernatant plasmawas collected from all samples and stored at 4° C. All supernatantplasma samples were tested for the production of leukotriene B₄ (LTB₄)using the LTB₄ enzyme immunosorbent assay (EIA) kit from Assay Designs(Ann Arbor, Mich., USA) according to the manufacturer's instructions.

Compounds of this invention may be prepared employing general syntheticprocedures known in the art, including methods described in U.S. Pat.No. 5,552,437 and PCT publication WO2004/108720, published Dec. 16,2004, both publications herein incorporated by reference in theirentirety. The synthetic routes outlined in the following methods,reaction schemes and Examples are provided for illustrative purposes.Groups designated “R” in the general schemes as well as solvents,temperatures and others reaction conditions may be selected or modifiedby one of ordinary skill in the art. Functional groups can be eitherprotected or converted to other functional groups. For example, aminogroups can be acylated with an acyl chloride or and anhydride with amild base such as K₂CO₃ or nitrogen base. Esters can be converted totertiary alcohols with a Grignard reagent or an alkyl lithium reagents.

Some abbreviations used herein include: Ac=acyl;AIBN=2,2′-azobisisobutyronitrile; BuLI is n-butyllithium; CAN=ceriumammonium nitrate; DAST=diethylaminosulfur trifluoride;DBU=1,8-diazabicyclo[5.4.0]undec-7-ene;DCC=1,3-dicyclohexylcarbodiimide; DCM=dichloromethane; DME=ethyleneglycol dimethyl ether; DMF=N,N-dimethylformamide; DMSO=dimethylsulfoxide; EtOH=ethanol; Et₂O=diethyl ether; Et₃N=triethylamine;EtOAc=ethyl acetate; h=hours; HOAc=acetic acid; KHMDS=potassiumbis(trimethylsilyl)amide; LAH=lithium aluminum hydride; LDA=lithiumdiisopropylamide; m-CPBA=3-chloroperoxybenzoic acid; MeOH=methanol;NBS=N-bromosuccinimide; NMO=4-methylmorpholine N-oxide;NMP=1-methyl-2-pyrrolidinone; OTf=trifluoromethanesulfonate=triflate;O-THP=O-tetrahydropyran-2-yl; PPTS=pyridinium p-toluenesulfonate;rt=room temperature; TBAF=tetrabutylammonium fluoride; Tf₂O=triflicanhydride; TFA=trifluoro acetic acid; THF=tetrahydrofuran;TMSCN=trimethylsilyl cyanide.

Oxadiazoles can be prepared, for example, according to literatureprocedures and references cited therein with the appropriate startingmaterial as follows: White, A. D., et. al. J. Med. Chem., (1996) 39,4382; Futaki, K., Tosa, S. Chem. Pharm. Bull. (1960) 8, 908; Chem.Abstr. (1966) 64, 3558a.

Thiadiazoles can be prepared, for example, according to literatureprocedures and references cited therein with the appropriate startingmaterial as follows: Werber, G. Buccheri, F. Marino, M. L., J. Hetero.Chem. (1975) 12, 581; Pandey, V. K. et. al., Ind. J. Chem. Sect. B(2003) 42, 2583; Shaban, M. A. E., Mostafa, M. A., Nasr, A. Z. Pharmazia(2003) 58, 6; Miyamoto, K., et al. Chem. Pharm. Bull. (1985) 33, 5126;Yokohama, S. et. al., Chem. Pharm. Bull. (1992) 40, 2391; White, A. D.et al. J. Med. Chem. (1996) 39, 4382; Bartels-Keith, J. R., Burgess, M.T., Stevenson, J. M. J. Org. Chem. (1977) 42, 3725.

METHOD A (see scheme below): Compound 1 is prepared according toprocedures described in U.S. Pat. No. 5,552,437 and WO2004/108720. Themethyl group is converted to the mono or dibromo 2 with NBS and heatingin an inert solvent such as CCl₄ in the presence of a radical initiatorsuch as benzoyl peroxide, AIBN or light. The monobromo compound 2 istreated with an excess of NMO at ca. 100° C. in a solvent like dioxaneuntil complete conversion to the aldehyde 8. Alternatively, the dibromoanalog of 2 treated with AgNO₃ in dioxane-water at reflux for a shorttime gave the aldehyde 8. The aldehyde 8 is also obtained from thedibromo analog of 2 with a hot solution of NH₄OAc in HOAc (water can beadded).

Compound 4 is prepared at rt from a mixture of 2 (monobromo) and 3 in aninert solvent such as DMF in the presence of a weak base such as K₂CO₃.The acetyl is removed with a base such as NH₄OH in THF-water to yieldcompound 5. The free NH is converted to N-alkyls, N-alkyloyls orN-arylolys with alkyl halides, aliphatic acyl halides or aromatic acylhalides through a mild base in an inert solvent such as DCM.

The double bond of coumarin 5 is reduced to the single bond withhydrogen under pressure (40-60 psi) and heating (40-60° C.) with acatalyst such as palladium on charcoal in a suitable solvent forhydrogenation like ethanol. The hydrogenation can be accomplished at anypoint of any sequence.

METHOD B (see scheme below): The aldehyde 8 and the amine 9 are refluxedtogether with or without an acid catalyst such as PPTS in a solvent thatforms an azeotrope such as toluene to yield the imine 10. This imine isreduced with NaBH₄ or the like to the free NH 5 in ethanol or methanol.If R²═OH, the imine 10 is treated with DAST in DCM at −78° C., broughtto rt and then poured into a solution of NaBH₄ in ethanol to afford thefluorinated analogue 11.

Alternatively, imine 10 is reacted with Grignard reagents between −95and −78° C. in THF or ether. The mixture is brought to 0° C. andquenched with NH₄Cl, to yield 12.

METHOD C (see scheme below): The coumarin 13 is treated with thiol 14and an inorganic base such as K₂CO₃ in DMF or NMP between 80-120° C. toafford compound 15. Alternatively, the thiol 14 is treated with KOH inmethanol for a few minutes and the solvent is removed to dryness. Tothis potassium salt is added the coumarin 13 in NMP and the mixture isheated to 80-120° C. to yield 15. The coumarin 16 is prepared from thepalladium catalyzed reaction of compound 13 in MeOH-DMSO (ca. 1:2) underan atmosphere of CO at 60° C. with a base such as triethylamine untilcompletion.

METHOD D (see scheme below): To a −78° C. THF solution of 17 is addedBuLi followed by chlorotrimethylsilane. The temperature is raised to−20° C., cooled back to −78° C. and BuLi is added followed by a reagenthaving a carbonyl group to furnish 18.

METHOD E (see scheme below): A solution of R-(methylthio)(thioxo)acetate20, where R is alkyl (see: Z. Chem. 1977, vol. 17, 366), andhydrazinecarbodithioic acid potassium salt 19 (see: J. Am. Chem. Soc.1983, 105, 2287) in EtOH is heated to reflux overnight. After cooling,the reaction mixture is extracted with Et₂O and the solvent removed. Theresidue is purified by flash column chromatography on silica gel to givecompound 21.

Method A

Method B

Method C

Method D

Method E

7-Bromo-4-trifluoromethanesulfonyloxycoumarin 25 can be prepared asshown below in Method F. Description of how to make 25 is also found inthe procedures described in U.S. Pat. No. 5,552,437 in Scheme 1 atcolumns 17-18 (see structure V) therein and in the section titled“Preparation Of Coumarins” starting at column 58 therein. Bromophenol 22can be acetylated by treating a mixture of 22 and acetyl chloride in thepresence of a base such as pyridine in a solvent such as dichloromethaneto yield the corresponding acetate which, upon heating neat with a Lewisacid such as aluminum chloride, gives the acyl derivative 23. Reactionof 23 with first an inorganic base such as sodium hydride in an organicsolvent such as benzene followed by addition of a carbonate such asdiethylcarbonate furnishes the intermediate 24. The intermediate 24 isthen transformed using trifluoromethanesulfonic anhydride, in thepresence of an amine such as triethylamine, in a neutral solvent such asdichloromethane, to the corresponding triflate 25.

Method F

Example 1A 7-(Bromomethyl)-4-(4-fluorophenyl)-2H-chromen-2-one Step 1: 4Hydroxy-7-methyl-2H-chromen-2-one

To a 80° C. suspension of NaH (60 g, 1500 mmol, 60%) in toluene wasadded 1-(2-hydroxy-4-methylphenyl)ethanone (100 g, 666 mmol; also knownas 2′-hydroxy-4′-methylacetophenone) in 800 mL of toluene over 1 h. Thiswas followed by the dropwise addition of diethyl carbonate (157 g, 1.3mol) in 1000 ml of toluene over 1 h. The reaction mixture was left at80° C. overnight. After cooling to rt, the solution was poured into 1.6L of HCl (2N). The precipitate formed was filtered, collected andstirred in MeOH (minimum amount). After filtration, the title compoundwas dried overnight (at 55° C., under high vacuum) to yield the titlecompound. ¹H NMR (400 MHz, DMSO-d₆): δ 12.45 (1H, s), 7.58 (1H, d), 7.13(2H, m), 6.53 (1H, s) and 2.39 (3H, s).

Step 2: 4-(4-fluorophenyl)-7-methyl-2H-chromen-2-one

To a −30° C. solution of 4 hydroxy-7-methyl-2H-chromen-2-one (50 g, 284mmol) and triethylamine (48.8 g, 482 mmol) was added Tf₂O (128.1 g, 454mmol) in 120 ml of CH₂Cl₂ very slowly (internal Temp. <−30° C.). After30 min of stirring the solution was brought to 0° C. and quenched withNH₄Cl. After extraction with CH₂Cl₂ the organic phase was washed withH₂O (3×), dried over MgSO₄ and the solvent removed. The solid obtainedwas stirred in hexane-ether (9/1). After filtration, the triflateintermediate was dried. ¹H NMR (400 MHz, acetone-d₆): δ 7.68 (1H, d),7.37 (2H, m), 6.61 (1H, s) and 2.52 (3H, s).

A mixture of the triflate (40 g, 130 mmol), p-fluorophenylboronic acid(21.8 g, 156 mmol), Pd(OAc)₂ (0.87 g, 3.9 mmol), tricyclohexylphosphine(1.31 g, 4.7 mmol) and potassium fluoride (24.9 g, 428 mmol) in 500 mLof THF was stirred at rt overnight. The mixture was filtered over celiteand the solvent removed. The crude product was then purified over asmall pad of silica gel using CH₂Cl₂. The solvent was removed and theresulting solid stirred with CH₂Cl₂-hexane (1/9). After filtration, theproduct was dried to yield the title compound. ¹H NMR (400 MHz,acetone-d₆): δ 7.62 (2H, m), 7.39 (3H, m), 7.25 (1H, s), 7.15 (1H, d),6.29 (1H, s) and 2.45 (3H, s).

Step 3: 7-(bromomethyl)-4-(4-fluorophenyl)-2H-chromen-2-one

A mixture of 4-(4-fluorophenyl)-7-methyl-2H-chromen-2-one (24.0, 94.3mmol), NBS (18.5 g, 103.8 mmol) and benzoyl peroxide (1.14 g, 4.72 mmol)in 470 mL of CCl₄ was brought to reflux. The solution was left overnightat reflux and then filtered hot. Once cooled to rt the solvent wasremoved, the compound was dissolved in CH₂Cl₂ and a purification wasdone with a small pad of silica gel using hexane-EtOAc (8/2) to (1/1).The solvent was removed and the solid triturated with hexane-EtOAc andfiltered to give the title compound. The remaining solvent was removedto give additional compound contaminated with some starting material anddibromo compound. ¹H NMR (400 MHz, acetone-d₆): δ 7.67 (2H, m), 7.55(1H, s), 7.50 (1H, d), 7.40 (3H, m), 6.40 (1H, s) and 4.75 (2H, s).

Example 1B4-(4-Fluorophenyl)-7-[({5-[(1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-oneStep 1: Methyl (2S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoate

To a solution of (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid(3.0 g, 17.4 mmol) in 60 ml of ether was added a solution ofdiazomethane in ether until a yellow coloration remained. The reactionmixture was then stirred 30 min at room temperature and concentrated todryness to afford the title compound. ¹H NMR (400 MHz, acetone-d₆): δ5.67 (s, 1H), 3.85 (s, 3H), 1.57 (s, 3H).

Step 2: (2S)-3,3,3-Trifluoro-2-hydroxy-2-methylpropanohydrazide

To a solution of methyl(2S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoate (3.26 g, 19.0 mmol)was added hydrazine monohydrate (2.1 ml). The mixture was heated at 130°C. for 90 min and cooled down to room temperature. After evaporation todryness, the residue was purified on a small bed of silica gel (100%EtOAc) to afford the title compound.

Step 3: (2S)-2-(5-Amino-1,3,4-oxadiazol-2-yl)-1,1,1-trifluoropropan-2-ol

To a solution of (2S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanohydrazide(3.0 g, 17.5 mmol) in water (17 mL) was added cyanogen bromide (1.87 g,17.7 mmol) and potassium bicarbonate (1.82 g, 18.1 mmol). The reactionmixture was stirred 30 min at rt until a white precipitate was formed.The precipitate was filtered and washed with water followed by a mixtureof ether-hexanes (1:1) to afford the title compound. ¹H NMR (400 MHz,acetone-d6): δ 6.57 (bs, 2H), 6.20 (bs, 1H), 1.80 (s, 3H).

Step 4: 4-(4-Fluorophenyl)-2-oxo-2H-chromene-7-carbaldehyde

7-(Bromomethyl)-4-(4-fluorophenyl)-2H-chromen-2-one can be prepared asdescribed in Example 1A; its preparation is also described in U.S. Pat.No. 5,552,437. 7-(Bromomethyl)-4-(4-fluorophenyl)-2H-chromen-2-one(11.42 g, 34.3 mmol) and NMO (13.9 g, 102.8 mmol) in 110 mL of dioxanewere heated to reflux for 6 h. The solution was cooled to rt and thesolvent removed. The crude compound was diluted in EtOAc and washed withNH₄Cl_(aq), water, brine and dried over MgSO₄. The solvent was removedto yield the title compound. ¹H NMR (400 MHz, acetone-d₆): δ 10.20 (1H,s), 7.95 (1H, s), 7.85 (1H, m), 7.68 (3H, m), 7.38 (2H, m) and 6.51 (1H,s).

Step 5:4-(4-Fluorophenyl)-7-[({5-[(1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one

A solution of the previous aldehyde (210 mg, 0.78 mmol),(2S)-2-(5-amino-1,3,4-oxadiazol-2-yl)-1,1,1-trifluoropropan-2-ol (200mg, 1.02 mmol) and PPTS (20 mg, 0.08 mmol) in 2 ml of toluene was heatedunder reflux with a Dean-Stark trap for 4 h. The reaction mixture wascooled down and concentrated to dryness. Dry ethanol (2 ml) was thenadded and the mixture cooled to 0° C. Sodium borohydride (30 mg, 0.78mmol) was added and the resulting mixture was stirred at 0° C. for 30min. The reaction mixture was partitioned between aqueous NH₄Cl andEtOAc. The organic phase was washed with brine, dried over anhydrousMgSO₄, concentrated and purified on silica gel column(chloroform-ethanol; 95:5) to give the title compound. ¹H NMR (400 MHz,acetone-d₆): δ 7.65 (m, 2H), 7.5 (m, 3H), 7.39 (m, 3H), 6.35 (s, 1H),6.22 (s, 1H), 4.70 (d, 2H, J=6 Hz), 1.81 (s, 3H).

Example 24-(4-Fluorophenyl)-7-[({5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-6-methyl-2H-chromen-2-oneStep 1: 3-Bromo-4-methylanisole

To a suspension of 5-methoxy-2-methylaniline (5.00 g, 36.4 mmol) inwater (144 mL) at 10° C., was added conc. H₂SO₄ (56 mL), whilemaintaining internal temperature below 25° C. After 1 h at rt, themixture was cooled to 3° C. and a solution of sodium nitrite (3.77 g,54.7 mmol) in water (20 mL) was added dropwise over 30 min, keeping theinternal temperature below 5° C. After 1 h at 3° C., the yellowheterogeneous mixture was poured into a 5° C. solution of CuBr (52.0 g,364 mmol) in 48% aqueous HBr (260 mL). The dark mixture was heated at60° C. for 2 h, allowed to cool to rt and extracted with Et₂O (3×)(solid Na₂S₂O₃ was added in the extraction process for partialdecoloration). The combined organics were washed with 1 N NaOH (3×), 10%aq. Na₂S₂O₃ and brine, dried (Na₂SO₄) and concentrated, affording thetitle compound as an orange liquid which was used without furtherpurification in the next Step. ¹H NMR (500 MHz, acetone-d₆): δ 7.24 (d,1H), 7.14 (d, 1H), 6.87 (dd, 1H), 3.80 (s, 3H), 2.31 (s, 3H).

Step 2: (4-Bromo-2-methoxy-5-methylphenyl)(4-fluorophenyl)methanone

4-Fluorobenzoyl chloride (1.40 mL, 11.9 mmol) was added dropwise to asuspension of AlCl₃ (1.73 g, 13.0 mmol) in 1,2-dichloroethane (30 mL) atroom temperature. After 15 min a solution of 3-bromo-4-methylanisole(2.17 g, 10.8 mmol) in 1,2-dichloroethane (3 mL) was added dropwise. Theresulting mixture was stirred for 2 h, poured into 200 mL of ice-water,stirred for 20 min and extracted with CHCl₃ (3×). The combined organicswere washed with 5% aq. NaHCO₃, brine, dried (Na₂SO₄) and concentrated.The residue was subjected to chromatography on silica gel (EtOAc-hexane,5:95) affording the title compound. ¹H NMR (500 MHz, acetone-d₆): δ 7.86(m, 2H), 7.38 (s, 1H), 7.31-7.26 (m, 3H), 3.76 (s, 3H), 2.39 (s, 3H).

Step 3: (4-Bromo-2-hydroxy-5-methylphenyl)(4-fluorophenyl)methanone

A solution of(4-bromo-2-methoxy-5-methylphenyl)(4-fluorophenyl)methanone (1.80 g,5.57 mmol) in CH₂Cl₂ (6 mL) was added over 10 min to a 0° C. solution ofBBr₃ (1.05 mL, 11.1 mmol) in the same solvent (14 mL) and the resultingmixture was stirred at 0° C. After 1.5 h, the reaction mixture waspoured into 200 mL of ice-water, vigorously stirred for 10 min andextracted with CHCl₃ (3×). The combined organic extracts were washedwith water and brine, dried (Na₂SO₄) and concentrated, affording thetitle compound. ¹H NMR (500 MHz, acetone-d₆): δ 11.46 (s, 1H), 7.88 (m,2H), 7.58 (s, 1H), 7.37 (m, 2H), 7.32 (s, 1H), 2.34 (s, 3H).

Step 4: 7-Bromo-4-(4-fluorophenyl)-6-methyl-2H-chromen-2-one

(4-Bromo-2-hydroxy-5-methylphenyl)(4-fluorophenyl)methanone (1.61 g,5.21 mmol) and methyl (triphenylphosphoranylidene)acetate (2.26 g, 6.77mmol) were heated in refluxing toluene (15 mL) for 24 h. The reactionmixture was allowed to cool to rt and concentrated. The yellow solidobtained was subjected to column chromatography on silica gel(EtOAc-toluene, 0% to 2%) to afford the title compound. ¹H NMR (500 MHz,acetone-d₆): δ 7.70 (s, 1H), 7.66 (m, 2H), 7.46 (s, 1H), 7.39 (m, 2H),6.39 (s, 1H), 2.40 (s, 3H).

Step 5: Methyl4-(4-fluorophenyl)-6-methyl-2-oxo-2H-chromene-7-carboxylate

DMSO (17 mL) and Et₃N (0.828 mL, 5.94 mmol) were successively added to asuspension of 7-bromo-4-(4-fluorophenyl)-6-methyl-2H-chromen-2-one(0.990 g, 2.97 mmol) and Pd(dppf)Cl₂.CH₂Cl₂ (0.485 g, 0.594 mmol) inMeOH (10 mL). The mixture was heated at 65° C., under an atmosphere ofcarbon monoxide for 18 h. The reaction mixture was allowed to cool tort, poured into water (200 mL) and extracted with CHCl₃ (3×). Thecombined organic extracts were washed with water and brine, dried(Na₂SO₄) and concentrated. The residue was subjected to columnchromatography on silica gel (EtOAc-toluene, 3% to 5%) to afford thetitle compound. ¹H NMR (500 MHz, acetone-d₆): δ 7.85 (s, 1H), 7.69 (m,2H), 7.44 (s, 1H), 7.40 (m, 2H), 6.47 (s, 1H), 3.94 (s, 3H), 2.54 (s,3H).

Step 6: 4-(4-Fluorophenyl)-6-methyl-2-oxo-2H-chromene-7-carboxylic acid

To a solution of methyl4-(4-fluorophenyl)-6-methyl-2-oxo-2H-chromene-7-carboxylate (0.722 g,2.31 mmol) in THF (23 mL) was added a 1 N solution of LiOH (11.6 mL,11.6 mmol), and the mixture was heated at 65° C. for 16 h. At roomtemperature, the mixture was neutralized with 1 N HCl and concentrated.The residue was stirred with THF (25 mL) and 2 N HCl (50 mL) for 16 h.The precipitate produced was collected by filtration, rinsed with waterand dried, affording the title compound that was used without furtherpurification. ¹H NMR (500 MHz, DMSO-d₆): δ 13.40 (br s, 1H), 7.80 (s,1H), 7.64 (m, 2H), 7.44 (m, 2H), 7.32 (s, 1H), 6.54 (s, 1H), 2.48 (s,3H).

Step 7: 4-(4-Fluorophenyl)-7-(hydroxymethyl)-6-methyl-2H-chromen-2-one

Isobutyl chloroformate (0.775 mL, 5.97 mmol) was added dropwise to4-(4-fluorophenyl)-6-methyl-2-oxo-2H-chromene-7-carboxylic acid (0.594g, 1.99 mmol) and Et₃N (1.11 mL, 7.96 mmol) in THF (13 mL) at 0° C.After 1 h, a freshly prepared solution of NaBH₄ 0.377 g, 9.96 mmol) inwater (10 mL) was added rapidly. The reaction mixture was stirred at 0°C. for 1 h, quenched using saturated. NH₄Cl and extracted with EtOAc(3×). The combined organic extracts were washed with 1 N HCl, 5% NaHCO₃and brine, dried (Na₂SO₄) and concentrated. The residue was subjected tocolumn chromatography on silica gel (EtOAc-CHCl₃, 30:70, then 35:65,then 40:60) to afford the title compound. ¹H NMR (400 MHz, acetone-d₆):δ 7.65 (m, 2H), 7.53 (s, 1H), 7.38 (m, 2H), 7.26 (s, 1H), 6.30 (s, 1H),4.76 (d, 2H), 4.55 (t, 1H), 2.26 (s, 3H).

Step 8: 4-(4-Fluorophenyl)-6-methyl-2-oxo-2H-chromene-7-carbaldehyde

4-(4-Fluorophenyl)-7-(hydroxymethyl)-6-methyl-2H-chromen-2-one (0.487 g,1.71 mmol) in CH₂Cl₂ (350 mL) was stirred with activated MnO₂ (2.23 g,25.7 mmol) for 65 h at rt. The reaction mixture was filtered through apad of celite and the filtrate was concentrated to afford the titlecompound. ¹H NMR (500 MHz, acetone-d₆): δ 10.40 (s, 1H), 7.86 (s, 1H),7.70 (m, 2H), 7.46 (s, 1H), 7.42 (m, 2H), 6.53 (s, 1H), 2.66 (s, 3H).

Step 9:4-(4-Fluorophenyl)-7-[({5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-6-methyl-2H-chromen-2-one

In a round-bottom flask fitted with a condenser and a Dean-Stark trap,4-(4-fluorophenyl)-6-methyl-2-oxo-2H-chromene-7-carbaldehyde (0.357 g,1.26 mmol) and2-(5-amino-1,3,4-oxadiazol-2-yl)-1,1,1-trifluorobutan-2-ol (0.32 g, 1.52mmol) were heated in refluxing toluene (8 mL) for 2 h in the presence ofpyridinium p-toluenesulfonate (32 mg, 0.126 mmol). The mixture wasallowed to cool to room temperature and concentrated to dryness. Theresidue was dissolved in EtOH (6 mL), cooled to 0° C. and NaBH₄ (48.0mg, 1.26 mmol) was added. After 15 min. at 0° C., the reaction wasquenched with sat. NH₄Cl and extracted with EtOAc (3×). The combinedorganic extracts were washed with water and brine, dried (Na₂SO₄) andconcentrated. The residue was subjected to column chromatography onsilica gel (EtOH-CHCl₃, 3% to 4%) to afford the title compound. ¹H NMR(500 MHz, acetone-d₆): δ 7.66 (m, 2H), 7.46 (br s, 2H), 7.39 (m, 2H),7.33 (s, 1H), 6.32 (s, 1H), 6.09 (br s, 1H), 4.68 (d, 2H), 2.41 (s, 3H),2.24 (m, 1H), 2.10 (m, 1H), 1.00 (t, 3H).

Example 37-(2-{[5-(1-Ethyl-1-hydroxypropyl)-1,3,4-thiadiazol-2-yl]amino}ethyl)-4-(4-fluorophenyl)-2H-chromen-2-oneStep 1: 3-(5-Amino-1,3,4-thiadiazol-2-yl)pentan-3-ol

To a −78° C. solution of 2-amino-1,3,4-thiadiazole (commerciallyavailable) (2.5 g, 24.72 mmol) in THF (200 mL, 0.1M) was added firstn-butyllithium 1.6M hexanes (30.9 mL, 49.4 mmol) followed 15 min laterby chlorotrimethylsilane (6.27 mL, 49.4 mmol). The temperature raised to−20° C. for 15 min and cooled back to −78° C. More n-butyllithium 1.6Mhexanes (15.45 mL, 24.72 mmol) was added followed 15 min later by3-pentanone (2.62 mL, 24.72 mmol). The solution was then warmed to rt(overnight). The reaction mixture was quenched with a saturated NH₄Clsolution and THF was removed under vacuum. The aqueous phase wasextracted with EtOAc (3×) and the combined organic layers were washedwith brine, dried over MgSO₄ and concentrated. The crude residueobtained was purified by column chromatography (100% EtOAc) to yield thetitle compound. ¹H NMR (400 MHz, acetone-d₆): δ 6.3 (bs, 2H), 4.4 (bs,1H), 2.0-1.7 (m, 4H), 0.9 (t, 6H).

Step 2:7-(2-{[5-(1-Ethyl-1-hydroxypropyl)-1,3,4-thiadiazol-2-yl]amino}ethyl)-4-(4-fluorophenyl)-2H-chromen-2-one

A mixture of 3-(5-amino-1,3,4-thiadiazol-2-yl)pentan-3-ol (0.129 g,0.689 mmol), 4-(4-fluorophenyl)-2-oxo-2H-chromene-7-carbaldehyde (0.200g, 0.746 mmol) and acetic acid (7.94 μL, 0.138 mmol) in benzene (2.5 mL)was stirred overnight at reflux with a Dean-Stark trap. After cooling,the mixture was diluted in THF (5 mL) and sodium triacetoxyborohydride(0.731 g, 3.45 mmol) was added. The mixture was then stirred at 45° C.for 3 h. The reaction was quenched with a saturated NaHCO₃ solution andpartioned between EtOAc and water. The organic layer was dried overMgSO₄, filtered and concentrated. The crude residue obtained waspurified by column chromatography (Hexane-EtOAc-MeOH, 50:50:0 to 0:98:2)to yield the title compound. ¹H NMR (400 MHz, acetone-d₆): δ 8.7 (m,2H), 7.5 (s, 1H), 7.45 (s, 1H), 7.4 (m, 3H), 6.35 (s, 1H), 4.75 (s, 2H),4.5 (bs, 1H), 2.0-1.75 (m, 4H), 0.9 (t, 6H).

Example 47-({[5-(1-Ethyl-1-fluoropropyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-4-(4-fluorophenyl)-2H-chromen-2-oneStep 1a: 3-(5-Amino-1,3,4-oxadiazol-2-yl)pentan-3-ol

To a solution of ethyl magnesium bromide (200 mmol) in 300 mL of THF at0° C. was added a suspension of ethyl5-amino-1,3,4-oxadiazol-2-carboxylate (8.00 g, 50.9 mmol; ChemicalAbstract, 1966, 64, 3558a) in THF. The reaction mixture was brought tort and 30 min later quenched with NH₄Cl. After extraction with EtOAc anddrying over MgSO₄, the solvent was removed. The crude product thusobtained was triturated, filtered and dried to yield the title compound.

Step 1b: 3-(5-Amino-1,3,4-oxadiazol-2-yl)pentan-3-ol

A mixture of methyl 2-ethyl-2-hydroxybutanoate (19.7 g, 134.7 mol) andhydrazine hydrate (14 mL) was heated to 130° C. for 4 h. The mixture wascooled to rt and excess reagent removed under vacuum to yield of thehydrazide. To this hydrazide and KHCO₃ (13.8 g, 138 mmol) in 150 mL ofwater was added portionwise BrCN (13.8 g, 131 mmol). After 90 min ofstirring, the white solid was filtered, washed with ether and dried toyield the title compound. ¹H NMR (400 MHz, acetone-d₆): δ 6.20 (bs, 2H),4.25 (s, 1H), 1.85 (m, 4H), 0.88 (t, 6H).

Step 2:7-({[5-(1-Ethyl-1-hydroxypropyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-4-(4-fluorophenyl)-2H-chromen-2-one

A mixture of 3-(5-amino-1,3,4-oxadiazol-2-yl)pentan-3-ol (0.446 g, 2.6mmol) and 4-(4-fluorophenyl)-2-oxo-2H-chromene-7-carbaldehyde (0.350 g,1.3 mmol) in 5 mL of toluene was refluxed with a Dean-Stark trapovernight. After cooling to rt the solvent was removed and the crudeimine diluted in ethanol (8 ml) at 0° C. Solid NaBH₄ (49 mg) was addedto the solution and after 30 min of stirring aqueous NH₄Cl was added todestroy the excess hydride. After dilution with EtOAc-brine, the organicphase was dried with MgSO₄. Purification on silica gel withtoluene-EtOAc (2:8) gave the title compound. ¹H NMR (400 MHz,acetone-d₆): δ 7.67 (m, 2H), 7.48 (m, 2H), 7.37 (m, 3H), 7.19 (bt, 1H),6.33 (s, 1H), 4.66 (m, 2H), 4.31 (s, 1H), 1.85 (m, 4H), 0.85 (t, 6H).

Step 3:7-({[5-(1-Ethyl-1-fluoropropyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-4-(4-fluorophenyl)-2H-chromen-2-one

A solution of imine obtained in the previous step (270 mg, 0.641 mmol)in CH₂Cl₂ was added dropwise to a solution of (diethylamino)sulphurtrifluoride (100 μL, 0.77 mmol) in CH₂Cl₂ precooled to −78° C. Thesolution was stirred at −78° C. 5 min, and warmed to room temperature.After 40 min at room temperature, the reaction mixture was decantedrapidly to a solution of NaBH₄ (0.20 g, 5.3 mmol) in EtOH (10 mL), andstirred vigorously at room temperature for 5 min. The reaction mixturewas partitioned between EtOAc and a saturated aq. solution ofNH₄OAc/NaCl. The phases were separated and the aqueous phase extractedwith EtOAc. The combined organic phases were dried over anhydrous MgSO₄,filtered and concentrated in vacuo. The residue was chromatographed onsilica gel (20-60% EtOAc/hexanes) to afford the title compound. ¹H NMR(400 MHz, CDCl₃): δ 7.60-7.67 (m, 2H), 7.43-7.52 (m, 3H), 7.34-7.40 (m,3H), 6.32 (s, 1H), 4.68 (d, 2H), 1.95-2.17 (m, 4H), 0.91 (t, 6H).

Example 57-(1-{[5-(1-Ethyl-1-hydroxypropyl)-1,3,4-oxadiazol-2-yl]amino}ethyl)-4-(4-fluorophenyl)-2H-chromen-2-one

To a solution of the imine, prepared as described in Example 4, step 2,(0.159 g, 0.37 mmol) in 5 mL of THF at −90° C. was added methylmagnesiumbromide (0.79 mmol). The reaction mixture was brought to 0° C. andquenched with NH₄Cl. After extraction with EtOAc, drying with MgSO₄, andevaporation, the crude material was purified on silica gel withtoluene-EtOAc (2:8) to yield the title compound. ¹H NMR (400 MHz,acetone-d₆) δ: 7.66 (m, 2H), 7.35-7.52 (m, 5H), 7.19 (d, 1H), 6.33 (s,1H), 4.95 (m, 1H), 4.23 (s, 1H), 1.72 (m 4H), 1.63 (d, 3H), 0.80 (m,6H).

Example 6A 7-bromo-4-pyridin-3-yl-2H-chromen-2-one can be prepared asfollows

Commercially available 7-hydroxy-4-(3-pyridyl)coumarin (1.48 g, 6.19mmol) and triphenylphosphine dibromide (5.22 g, 12.4 mmol) are heated ina sand bath at 320-350° C. for 1.5 h. The cooled solid is taken up withethanol (200 ml) and silica gel (100 g) and evaporated to dryness.Column chromatography (toluene/acetone; 80:20) affords7-bromo-4-pyridin-3-yl-2H-chromen-2-one.

Example 6B7-({5-[Dicyclopropyl(hydroxyl)methyl]-1,3,4-thiadiazol-2-yl}thio)-4-pyridine-3-yl-2H-chromen-2-oneStep 1: Ethyl (methylthio)(thioxo)acetate

To a mixture of sulfur (5.23 g, 163 mmol) in DMF (100 ml) was addedtriethylamine (34.1 ml, 245 mmol) and ethyl chloroacetate (10 g, 81.6mmol). After 3.5 h iodomethane (5.59 ml, 89.8 mmol) was added and themixture was stirred 1 h at rt. Et₂O-water was added and the organiclayer was separated. The organic phase was wash with water (3×), brine,dried over anhydrous Na₂SO₄ and the solvent removed to give the titlecompound which was used without further purification for the next step.¹H NMR (400 MHz, acetone-d₆): 4.38 (q, 2H), 2.72 (s, 3H), 1.34 (t, 3H).

Step 2: Ethyl 5-mercapto-1,3,4-thiadiazole-2-carboxylate

Ethyl (methylthio)(thioxo)acetate (20.0 g, 122 mmol) and potassiumhydrazinecarbodithioate (R. S. Drago et al., JACS (1983) 105, 2287)(17.8 g, 122 mmol) were reflux overnight in ethanol (500 ml). Thesolution was concentrated and EtOAc was added. The organic phase waswashed with 1M HCl, brine and dried over anhydrous Na₂SO₄. The solventwas evaporated and the residue purified on silica gel (hexanes-acetone,80:20) to give the title compound. ¹H NMR (400 MHz, acetone-d₆): 4.43(q, 2H), 1.38 (t, 3H).

Step 3: Dicyclopropyl(5-mercapto-1,3,4-thiadiazol-2-yl)methanol

To a solution of cyclopropylmagnesiumbromide (37 ml, 0.5 M/THF, 18.4mmol at 0° C. was slowly added a THF solution of ethyl5-mercapto-1,3,4-thiadiazole-2-carboxylate (1 g, 5.3 mmol). When halfthe solution was added, the cooling bath was removed and the rest of thesolution was added. The mixture was stirred at room temperature for 4hours then partitioned between aqueous NH₄Cl and Et₂O. The layers wereseparated and the aqueous phase was extracted with Et₂O. The combinedorganic layers were washed with brine and dried over anhydrous Na₂SO₄.The solvent was evaporated and the residue chromatographed on silica gel(hexanes:acetone, 95:5) to give the title compound. ¹H NMR (400 MHz,acetone-d₆): 4.75 (s, 1H), 1.39-1.26 (m, 2H), 0.67-0.38 (m, 8H).

Step 4:7-({5-[Dicyclopropyl(hydroxyl)methyl]-1,3,4-thiadiazol-2-yl}thio)-4-pyridine-3-yl-2H-chromen-2-one

KOH (0.089 g, 1.59 mmol) was added to a solution ofdicyclopropyl(5-mercapto-1,3,4-thiadiazol-2-yl)methanol (0.363 g, 1.60mmol) in dry MeOH. When a solution was obtained, the reaction mixturewas concentrated to dryness. Dry toluene was then added and the mixturewas concentrated to dryness again. The residue was dissolved in NMP,7-bromo-4-pyridin-3-yl-2H-chromen-2-one (400 mg, 1.32 mmol) was addedand the resulting mixture was stirred at 120° C. for 16 h. The reactionmixture was cooled and partitioned between aqueous NH₄OAc and EtOAc. Theorganic phase was washed with brine, dried over anhydrous Na₂SO₄,concentrated and purified on silica gel column (toluene-acetone, 90:10to 70:30) to give the title compound. ¹H NMR (400 MHz, CDCl₃): δ 8.82(d, 1H), 8.72 (s, 1H), 7.81 (dt, 1H), 7.64 (s, 1H), 7.58-7.50 (m, 1H),7.48-7.41 (m, 2H), 6.46 (s, 1H), 2.57 (s, 1H), 1.40-1.31 (m, 2H),0.69-0.57 (m, 6H), 0.50-0.44 (m, 1H).

Example 7 (+) and(−)-4-(4-Fluorophenyl)-7-[({5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-oneStep 1: Ethyl 2-hydroxy-2-(trifluoromethyl)butanoate

To a −78° C. solution of ethyl trifluoropyruvate (129.0 g 758 mmol) inether was added dropwise within 90 min a solution of EtMgBr 3.0 M inether (252 mL). The solution was brought over one 1 h to ca. −10° C. andpoured over 2 L of saturated NH₄Cl. The layers were separated and theaqueous phase extracted with ether (3×500 mL). The organic phases werecombined, dried over MgSO4 and the solvent removed. Distillation at50-65° C. (30 mm Hg) gave the title compound. ¹H NMR (400 MHz,acetone-d₆): δ 5.4 (s, 1H), 4.35 (q, 2H), 2.07 (m, 1H), 1.83 (m, 1H),1.3 (t, 3H) and 0.93 (t, 3H).

Step 2: 2-Hydroxy-2-(trifluoromethyl)butanohydrazide

The ethyl ester of step 1 (50.04 g, 250 mmol) and hydrazine hydrate(25.03 g, 50 mmol) were heated at 80° C. for 18 h. The excess hydrazinewas removed under vacuum and the crude product was filtered through apad of silica gel with EtOAc-Hexane (ca. 3 L) to furnish the titlecompound. ¹H NMR (400 MHz, acetone-d₆): δ 9.7 (s, 1H), 6.10 (s, 1H),2.25 (m, 1H), 1.85 (m, 1H) and 0.95 t, (3H).

Step 3: 2-(5-Amino-1,3,4-oxadiazol-2-yl)-1,1,1-trifluorobutan-2-ol

To hydrazide (34.07 g, 183 mmol) of step 2 in 275 mL of water was addedKHCO₃ (18.33 g, 183 mmol) followed by BrCN (19.39 g, 183 mmol)portionwise. After 3 h, the solid was filtered, washed with cold waterand dried to afford the title compound. Additional compound could berecovered from the aqueous phase by extraction (ether-hexane, 1:1). ¹HNMR (400 MHz, acetone-d₆): δ 6.54 (s, 2H), 6.01 (s, 1H), 2.22 (m, 1H),2.08 (m, 1H) and 0.99 (m, 3H).

Step 4:4-(4-Fluorophenyl)-7-[({5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one

A mixture of oxadiazole (14.41 g, 68.2 mmol) of step 3 and4-(4-fluorophenyl)-2-oxo-2H-chromene-7-carbaldehyde (14.1 g, 52.5 mmol)in toluene (160 mL) with 10% of PPTS was brought to reflux and let goovernight. The system was equipped with a Dean-Stark trap to collectwater. The solvent was removed and the crude oil (¹H NMR (400 MHz,acetone-d₆): δ 9.33 (1H, s, imine)) obtained was diluted in EtOH (ca. 75mL) at 0° C. To this solution was added NaBH₄ (1.9 g) portionwise andthe reaction was quenched with a solution of NH₄Cl after 45 min. Themixture was saturated with NaCl and extracted with EtOAc (3×200 mL). Theorganic phases were combined and dried over MgSO₄. Purification oversilica gel chromatography using toluene-EtOAc (55:45) gave the titlecompound. ¹H NMR (400 MHz, acetone-d₆): δ 7.65 (m, 2H), 7.50 (m, 3H),7.38 (m, 3H), 6.35 (s, 1H), 6.06 (s, 1H), 4.70 (m, 2H), 2.21 (m, 1H),2.11 (m, 1H) and 0.98 (t, 3H).

Step 5: Separation on chiral HPLC column of (+) and (−) enantiomers of4-(4-fluorophenyl)-7-[({5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one

A solution of(±)-4-(4-fluorophenyl)-7-[({5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one(0.5-0.6 g) in EtOH-Hexane (30:70, ca. 40 mL) was injected onto aCHIRALPAK AD® preparative (5 cm×50 cm) HPLC column (eluting withEtOH/Hexane, 30/70 with UV detection at 280 nm). The enantiomers wereseparated with the faster eluting enantiomer having a retention time of˜34 min for the (−)-enantiomer and the slower eluting enantiomer havinga retention time of ˜49 min for the (+)-enantiomer.

Example 84-(4-Fluorophenyl)-7-{[{5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}(methyl)amino]methyl}-2H-chromen-2-oneStep 1:4-(4-Fluorophenyl)-7-{[{5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}(methyl)amino]methyl}-2H-chromen-2-one

The (−) isomer of4-(4-fluorophenyl)-7-[({5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one(0.100 g, 0.22 mmol), methyl iodide (2 mL) and K₂CO₃ (0.061 g 0.44 mmol)were heated at 50° C. until the disappearance of starting material. Themixture was cooled to rt and diluted with EtOAc-water. The organic layerwas separated, dried and the solvent removed. Purification on silica gel(toluene-acetone, 8:2) gave the title compound. ¹H NMR (400 MHz,acetone-d₆): δ 7.68 (m, 2H), 7.51 (d, 1H), 7.48 (s, 1H), 7.39 (m, 3H),6.49 (s, 1H), 6.12 (s, 1H), 4.8 (q, 2H), 3.17 (s, 3H), 2.26 (m, 1H),2.09 (m, 1H), 1.02 (t, 3H).

Example 9A 7-bromo-4-(2-methyl-1,3-thiazol-4-yl)-2H-chromen-2-one can beprepared as follows

Step 1: 7-bromo-4-(1-ethoxyvinyl)-2H-chromen-2-one

To a solution of 7-bromo-4-trifluoromethanesulfonyloxycoumarin (5.1 g,13.7 mmol) in dioxane is added tributyl(1-ethoxyvinyl)tin (4.8 mL, 14.2mmol), (Ph₃P)₄Pd (0.790 g, 0.7 mmol) and LiCl (1.74 g, 41 mmol). Themixture is refluxed for 4 h, cooled and partitioned between aqueousNH₄Cl and EtOAc. The layers are separated and the aqueous phase isextracted with EtOAc. The combined organic layers are washed with brineand dried over anhydrous Na₂SO₄. The solvent is evaporated and theresidue is chromatographed on silica gel (CH₂Cl₂/EtOAc; 95:5) andtriturated in hexane/Et₂O to give the title compound.

Step 2: 7-bromo-4-(bromoacetyl)-2H-chromen-2-one

To a solution of 7-bromo-4-(1-ethoxyvinyl)-2H-chromen-2-one (2.0 g, 6.8mmol) in THF and H₂O is added N-bromosuccinimide (1.3 g, 14.2 mmol) withstirring for 30 min. Toluene is added and the solvent is evaporated. Theresidue is chromatographed on silica gel (hexane/EtOAc; 80:20) to givethe title compound.

Step 3: 7-bromo-4-(2-methyl-1,3-thiazol-4-yl)-2H-chromen-2-one

To a solution of 7-bromo-4-(bromoacetyl)-2H-chromen-2-one (0.605 g, 1.7mmol) in DMF is added thioacetamide (0.138 g, 1.8 mmol). The mixture isstirred 24 h at rt and at 100° C. overnight. Once cool to rt, it ispartitioned between aqueous NH₄Cl and EtOAc. The layers are separatedand the aqueous phase is extracted with EtOAc. The combined organiclayers are washed with brine and dried over anhydrous Na₂SO₄. Thesolvent is evaporated and the residue swished in hexanes/Et₂O to givethe title compound.

Example 9B7-[({5-[1-Hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]4-(2-methyl-1,3-thiazol-4-yl)-2H-chromen-2-oneStep 1: Methyl4-(2-methyl-1,3-thiazol-4-yl)-2-oxo-2H-chromene-7-carboxylate

To a solution of 7-bromo-4-(2-methyl-1,3-thiazol-4-yl)-2H-chromen-2-one(1.17 g, 3.63 mmol) in DMSO (21 ml) and methanol (12 ml) was addedtriethylamine (1.0 mL, 7.26 mmol) and [Pd(dppf)Cl₂]₂—CH₂Cl₂ (0.593 g,0.73 mmol). The reaction mixture was stirred overnight at 65° C. with aballoon of carbon monoxide. After cooling to rt, the reaction mixturewas diluted with EtOAc-CH₂Cl₂ (9:1) washed with water (3×) and brine.The organic phase was dried over MgSO₄ and evaporated to dryness. Theresidue was purified on silica gel (hexanes-EtOAc, 8:2) to afford thetitle compound. ¹H NMR (400 MHz, acetone-d₆): δ 8.45 (m, 1H), 8.12 (s,1H), 7.92 (m, 2H), 6.80 (s, 1H), 3.97 (s, 3H), 2.85 (s, 3H).

Step 2: 4-(2-Methyl-1,3-thiazol-4-yl)-2-oxo-2H-chromene-7-carboxylicacid

To a solution of methyl4-(2-methyl-1,3-thiazol-4-yl)-2-oxo-2H-chromene-7-carboxylate (1.0 g,3.32 mmol) in THF (33 ml) was added lithium hydroxide 1 M (16.6 ml, 16.6mmol). The reaction was heated at 65° C. for 90 min, cooled to rt andevaporated. A solution of HCl 2N was then added to the residue and themixture stirred for 1 h. The powder was filtered to give the titlecompound. ¹H NMR (400 MHz, DMSO-d₆): δ 8.37 (m, 1H), 8.28 (s, 1H), 7.87(m, 2H), 6.85 (s, 1H), 2.80 (s, 3H).

Step 3: 7-(Hydroxymethyl)-4-(2-methyl-1,3-thiazol-4-yl)-2H-chromen-2-one

To a solution of4-(2-methyl-1,3-thiazol-4-yl)-2-oxo-2H-chromene-7-carboxylic acid (0.692g, 2.41 mmol) in THF (16 ml) at 0° C. was added triethylamine (1.3 ml,9.63 mmol) followed by isobutyl chloroformate (0.94 ml, 7.23 mmol) over15 min. The reaction mixture was stirred at 0° C. for 1 h and sodiumborohydride (0.456 g, 12.0 mmol) in water (12 ml) was added. Thereaction mixture was stirred 1 h at 0° C., quenched with a solution ofNH₄Cl and extracted with EtOAc. The organic phase was washed with brine,dried over MgSO₄ and evaporated to dryness. The residue was purified bychromatography on silica gel (hexanes-EtOAc, 4:6 to 2:8) to give thetitle compound. ¹H NMR (400 MHz, acetone-d₆): δ 8.22 (m, 1H), 8.05 (s,1H), 7.40 (s, 1H), 7.35 (m, 1H), 6.62 (s, 1H), 4.80 (m, 2H), 4.55 (m,1H), 2.82 (s, 3H).

Step 4: 4-(2-Methyl-1,3-thiazol-4-yl)-2-oxo-2H-chromene-7-carbaldehyde

To a solution of7-(hydroxymethyl)-4-(2-methyl-1,3-thiazol-4-yl)-2H-chromen-2-one (0.387g, 1.42 mmol) in CH₂Cl₂ (7 ml) was added MnO₂ (1.85 g, 21.2 mmol) andstirred at rt for 4 h. A second portion of MnO₂ (1.85 g, 21.2 mmol) wasadded and 3 h later the reaction mixture was filtered on celite,evaporated to dryness and purified by trituration in CH₂Cl₂-MeOH (9:1)to give the title compound. ¹H NMR (400 MHz, acetone-d₆): δ 10.12 (s,1H), 8.45 (m, 1H), 8.31 (s, 1H), 7.95 (s, 1H), 7.85 (m, 1H), 6.9 (s,1H), 2.80 (s, 3H).

Step 5:7-[({5-[1-Hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-4-(2-methyl-1,3-thiazol-4-yl)-2H-chromen-2-one

To a solution of4-(2-methyl-1,3-thiazol-4-yl)-2-oxo-2H-chromene-7-carbaldehyde (0.200 g,0.74 mmol) and2-(5-amino-1,3,4-oxadiazol-2-yl)-1,1,1-trifluorobutan-2-ol (0.202 g,0.96 mmol) in toluene (2 ml) was added PPTS (0.019 g, 0.07 mmol). Thereaction mixture was heated under reflux with a Dean-Stark trap for 6 h.After evaporation, the residue was diluted in EtOH (2 ml), cooled to 0°C. and sodium borohydride (28 mg, 0.74 mmol) was added. After 15 min,the reaction was quenched with a saturated solution of NH₄Cl, extractwith EtOAc then washed with water and brine. The solvent was evaporatedand the residue chromatographed on silica gel (chloroform-ethanol, 95:5)to give the title compound. ¹H NMR (400 MHz, acetone-d₆): δ 8.27 (d,1H), 8.09 (s, 1H), 7.45 (m, 3H), 6.66 (s, 1H), 6.08 (s, 1H), 4.7 (d,2H), 2.83 (s, 3H), 2.22 (m, 1H), 2.10 (m, 1H), 0.98 (m, 3H).

1. A compound of structural Formula Ia

and the pharmaceutically acceptable salts, esters and solvates thereofwherein:

is selected from a single and a double bond; “A” is selected from thegroup consisting of (a) a 5-membered aromatic ring containing (i) one ormore carbon atoms, (ii) one heteroatom selected from oxygen and sulfur,and (iii) zero, one, two or three nitrogen atoms, (b) a 5-memberedaromatic ring containing one or more carbon atoms and from one to fournitrogen atoms, (c) a 6-membered aromatic ring containing carbon atomsand one, two or three nitrogen atoms; (d) a bicyclic aromatic ringsystem selected from benzothienyl, indolyl, quinolinyl and naphthalenyl;(e) phenyl, and (f) CH₂— phenyl; and wherein A is optionally mono- ordi-substituted with a substituent independently selected at eachoccurrence from the group consisting of (i) —F (ii) —Cl, (iii)—C₁₋₃alkyl optionally substituted with one or more of halo, (iv)—OC₁₋₃alkyl optionally substituted with one or more of halo, (v)—OC₃₋₆cycloalkyl, (vi) —CH₂OH, (vii) —COOR¹, (viii) —CN and (ix)—NR¹⁰R¹¹; X is selected from —O— and —S—; Y is selected from: (a)—NR⁶—CHR⁷ and —NR⁸—C(O)— wherein the nitrogen in Y is linked to the5-membered heterocyclic moiety of Formula Ia and the carbon in Y islinked to the bicyclic heterocyclic moiety of Formula Ia; (b) —S— and(c) —O—; R¹ is selected from the group consisting of —H, —C₁₋₆ alkyl and—C₃₋₆ cycloalkyl; R² is selected from the group consisting of —H, —OH,—F, —C₁₋₃alkyl, —OC₁₋₃alkyl and —OC(O)—C₁₋₃alkyl; R³ is selected fromthe group consisting of —H, —C₁₋₆alkyl, —C₁₋₆alkyl substituted with oneor more of fluoro, —C₁₋₁₆alkyl substituted with R⁹, —C₂₋₆alkenyl,—C₃₋₆cycloalkyl, —C₅₋₇cycloalkenyl and -Z; R⁴ is selected from the groupconsisting of —H, —C₁₋₆alkyl, —C₁₋₆alkyl substituted with one or more offluoro, —C₁₋₆alkyl substituted with R⁹, —C₂₋₆alkenyl, —C₃₋₆cycloalkyl,—C₅₋₇cycloalkenyl and -Z; or R³ and R⁴ together represent oxo; or R³ andR⁴ are joined together with the carbon to which they are attached toform a ring selected from the group consisting of a —C₃₋₆cycloalkyl ringand a —C₅₋₇cycloalkenyl ring, provided that when R³ and R⁴ are joinedtogether with the carbon to which they are attached to form a—C₅₋₇cycloalkenyl ring, there is no double bond at the C-1 position inthe ring; or R², R³ and R⁴ are joined together with the carbon to whichthey are attached to form a cycloalkenyl ring selected from:

R⁵ is absent or is a substituent selected from the group consisting of—C₁₋₆ alkyl, —C₃₋₆ cycloalkyl and halo; R⁶ is selected from the groupconsisting of (a) —H, (b) —C₁₋₄ alkyl, (c) —C(O)C₁₋₄ alkyl, and (d)—C(O)phenyl optionally substituted with —C₁₋₄ alkyl; R⁷ is selected fromthe group consisting of (a) —H, (b) —C₁₋₄ alkyl, (c) —C₃₋₆cycloalkyl,(d) phenyl optionally mono- or di-substituted with a substituentindependently selected at each occurrence from the group consisting of—C₁₋₄ alkyl, —F and —Cl, and (e) a 5-membered aromatic ring containing(i) one or more carbon atoms, (ii) one heteroatom selected from oxygenand sulfur, and (iii) zero, one, two or three nitrogen atoms; R⁸ isselected from the group consisting of —H and —C₁₋₄ alkyl; R⁹ is selectedfrom the group consisting of —COOR¹, —C(O)H, —CN, —CR¹R¹OH, —OR¹,—S—C₁₋₆alkyl and —S—C₃₋₆ cycloalkyl; R¹⁰ is selected from the groupconsisting of —H, —C₁₋₆ alkyl, —C₃₋₆ cycloalkyl and —COOR¹; R¹¹ isselected from the group consisting of —H, —C₁₋₆ alkyl and —C₃₋₆cycloalkyl; and Z is selected from the group consisting of (a) a5-membered aromatic ring containing (i) one or more carbon atoms, (ii)one heteroatom selected from oxygen and sulfur, and (iii) zero, one, twoor three nitrogen atoms, (b) a 5-membered aromatic ring containing oneor more carbon atoms and from one to four nitrogen atoms, (c) a6-membered aromatic ring containing carbon atoms and one, two or threenitrogen atoms; (d) phenyl, and (e) —CH₂— phenyl and —CH₂-dioxolanyl,and wherein Z is optionally mono- or di-substituted with a substituentindependently selected at each occurrence from the group consisting of(i) —F, (ii) —Cl, (iii) —C₁₋₃alkyl optionally substituted with one ormore of halo, (iv) —OC₁₋₃alkyl optionally substituted with one or moreof halo, (v) —OC₃₋₆cycloalkyl, (vi) —CH₂OH, (vii) —COOR¹, (viii) —CN and(ix) —NR¹⁰R¹¹.
 2. The compound of claim 1 having structural Formula Ib

and the pharmaceutically acceptable salts, esters and solvates thereofwherein R¹² is selected from the group consisting of —H and —F; and R¹³is absent or is a substituent at the 3- or 4-position and is selectedfrom the group consisting of (i) —F, (ii) —Cl, (iii) —C₁₋₃alkyloptionally substituted with one or more of halo, (iv) —OC₁₋₃alkyloptionally substituted with one or more of halo, (v) —OC₃₋₆cycloalkyl,(vi) —CH₂OH, (vii) —COOR¹, (viii) —CN and (ix) —NR¹⁰R¹¹.
 3. The compoundof claim 2 having structural Formula I

and the pharmaceutically acceptable salts, esters and solvates thereof.4. The compound of claim 1 having structural Formula Ic

and the pharmaceutically acceptable salts, esters and solvates thereofwherein Y is selected from —S— and —O—; R¹² is selected from the groupconsisting of —H and —F; R¹³ is absent or is a substituent at the 3- or4-position and is selected from the group consisting of (i) —F, (ii)—Cl, (iii) —C₁₋₃alkyl optionally substituted with one or more of halofor example including —CF₃, (iv) —OC₁₋₃alkyl optionally substituted withone or more of halo for example including —OCHF₂ and —OCF₃, (v)—OC₃₋₆cycloalkyl, (vi) —CH₂OH, (vii) —COOR¹, (viii) —CN and (ix)—NR¹⁰R¹¹.
 5. The compound of claim 1 selected from the group consistingof:4-bromo-N-{[4-(4-fluorophenyl)-2-oxo-2H-chromen-7-yl]methyl}-N-{5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}benzamide;4-(4-fluorophenyl)-7-{[{5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}(isopropyl)amino]methyl}-2H-chromen-2-one;7-[({5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-4-(2-methyl-1,3-thiazol-4-yl)-2H-chromen-2-one;4-(4-fluorophenyl)-7-[({5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-6-methyl-2H-chromen-2-one;N-{[4-(4-fluorophenyl)-2-oxo-2H-chromen-7-yl]methyl}-N-{5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}acetamide;4-(4-fluorophenyl)-7-({[5-(1-hydroxy-1-phenylethyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-2H-chromen-2-one;4-(4-fluorophenyl)-7-[({5-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one;4-(4-fluorophenyl)-7-[({5-[(1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one;4-(4-fluorophenyl)-7-{[{5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}(methyl)amino]methyl}-2H-chromen-2-one;4-(4-fluorophenyl)-7-[({5-[(1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one;3-{7-[({5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2-oxo-2H-chromen-4-yl}benzonitrile;4-(4-fluorophenyl)-7-({[5-(2,2,3,3,3-pentafluoro-1-hydroxy-1-methylpropyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-2H-chromen-2-one;4-(4-fluorophenyl)-7-({[5-(1-hydroxycyclopentyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-2H-chromen-2-one;(R)-6-fluoro-4-(4-fluorophenyl)-7-[({5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one;(S)-6-fluoro-4-(4-fluorophenyl)-7-[({5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one;6-chloro-4-(4-fluorophenyl)-7-[({5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one;6-fluoro-4-(4-fluorophenyl)-7-[({5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one;4-(4-fluorophenyl)-7-[({5-[hydroxy(phenyl)methyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one;7-({[5-(1-ethyl-1-hydroxypropyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-6-fluoro-4-(4-fluorophenyl)-2H-chromen-2-one;4-(4-fluorophenyl)-7-({[5-(1-hydroxy-1-methylpropyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-2H-chromen-2-one;7-({[5-(1-ethylpropyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-4-(4-fluorophenyl)-2H-chromen-2-one;4-[3-(difluoromethoxy)phenyl]-7-({[5-(1-ethyl-1-hydroxypropyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-2H-chromen-2-one;4-(4-fluorophenyl)-7-[({5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one;(+)-4-(4-fluorophenyl)-7-[({5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one;(−)-4-(4-fluorophenyl)-7-[({5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one;7-({[5-(1-ethyl-1-hydroxypropyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-4-[3-(trifluoromethoxy)phenyl]-2H-chromen-2-one;6-chloro-7-({[5-(1-ethyl-1-hydroxypropyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-4-phenyl-2H-chromen-2-one;7-({[5-(1-ethyl-1-hydroxypropyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-4-(3-methylphenyl)-2H-chromen-2-one;7-(1-{[5-(1-ethyl-1-hydroxypropyl)-1,3,4-oxadiazol-2-yl]amino}ethyl)-4-(4-fluorophenyl)-2H-chromen-2-one;7-({[5-(1-ethyl-1-fluoropropyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-4-(4-fluorophenyl)-2H-chromen-2-one;7-{[(5-cyclobutyl-1,3,4-oxadiazol-2-yl)amino]methy}-4-(4-fluorophenyl)-2H-chromen-2-one;7-{[(5-cyclopentyl-1,3,4-oxadiazol-2-yl)amino]methyl}-4-(4-fluorophenyl)-2H-chromen-2-one;7-({[5-(1-ethyl-1-hydroxypropyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-4-(4-fluorophenyl)chroman-2-one;7-{[[5-(1-ethyl-1-hydroxypropyl)-1,3,4-oxadiazol-2-yl](methyl)amino]methyl}-4-(4-fluorophenyl)-2H-chromen-2-one;7-({[5-(1-ethyl-1-hydroxypropyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-4-(3-fluorophenyl)-2H-chromen-2-one;4-(2,4-difluorophenyl)-7-({[5-(1-ethyl-1-hydroxypropyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-2H-chromen-2-one;7-({[5-(1-ethyl-1-hydroxypropyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-4-(3-methoxyphenyl)-2H-chromen-2-one;7-({[5-(1-ethyl-1-hydroxypropyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-4-(4-methoxyphenyl)-2H-chromen-2-one;7-({[5-(1-ethyl-1-hydroxypropyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-4-phenyl-2H-chromen-2-one;7-[({5-[dicyclopropyl(hydroxy)methyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-4-(4-fluorophenyl)-2H-chromen-2-one;7-({[5-(1-ethyl-1-hydroxypropyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-4-(4-fluorophenyl)-2H-chromen-2-one;N-[5-(1-ethyl-1-hydroxypropyl)-1,3,4-oxadiazol-2-yl]-N-{[4-(4-fluorophenyl)-2-oxo-2H-chromen-7-yl]methyl}acetamide;7-({[5-(1-ethyl-1-hydroxypropyl)-1,3,4-thiadiazol-2-yl]amino}methyl)-4-(4-fluorophenyl)-2H-chromen-2-one;7-{[(5-tert-butyl-1,3,4-thiadiazol-2-yl)amino]methyl}-4-(4-fluorophenyl)-2H-chromen-2-one;7-({5-[dicyclopropyl(hydroxy)methyl]-1,3,4-thiadiazol-2-yl}thio)-4-pyridin-3-yl-2H-chromen-2-one;7-({5-[dicyclopropyl(hydroxy)methyl]-1,3,4-thiadiazol-2-yl}thio)-4-(4-fluorophenyl)-2H-chromen-2-one;7-{[5-(1-ethyl-1-hydroxypropyl)-1,3,4-thiadiazol-2-yl]thio}-4-(4-fluorophenyl)-2H-chromen-2-one;and the pharmaceutically acceptable salts, esters and solvates thereof.6. A compound of claim 1 selected from the group consisting of:7-[({5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-4-(2-methyl-1,3-thiazol-4-yl)-2H-chromen-2-one;4-(4-fluorophenyl)-7-[({5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-6-methyl-2H-chromen-2-one;4-(4-fluorophenyl)-7-[({5-[(1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one;3-{7-[({5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2-oxo-2H-chromen-4-yl}benzonitrile;6-fluoro-4-(4-fluorophenyl)-7-[({5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one;6-chloro-4-(4-fluorophenyl)-7-[({5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one;7-({[5-(1-ethyl-1-hydroxypropyl)-1,3,4-oxadiazol-2-yl]amino}methyl)-4-(3-fluorophenyl)-2H-chromen-2-one;4-(4-fluorophenyl)-7-[({5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one;(−)4-(4-fluorophenyl)-7-[({5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one;and the pharmaceutically acceptable salts, esters and solvates thereof.7. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim 1 and a pharmaceutically acceptablecarrier.
 8. A method of preventing the synthesis, the action, or therelease of leukotrienes in a mammal which comprises administering tosaid mammal an effective amount of a compound of claim
 1. 9. The methodof claim 9 wherein the mammal is a human.
 10. A method of treating aninflammatory condition in a mammal which comprises administering to amammal in need of such treatment a therapeutically effective amount of acompound of claim
 1. 11. A method of treating atherosclerosis comprisingadministering a therapeutically effective amount of a compound of claim1 to a patient in need of such treatment.
 12. A method for preventing orreducing the risk of developing atherosclerosis, comprisingadministering a prophylactically effective amount of a compound of claim1 to a patient at risk for developing atherosclerosis.
 13. A method forpreventing or reducing the risk of an atherosclerotic disease eventcomprising administering a prophylactically effective amount of acompound of claim 1 to a patient at risk for having an atheroscleroticdisease event.
 14. A method for halting or slowing atheroscleroticplaque progression, comprising administering a therapeutically effectiveamount of a compound of claim 1 to a patient in need of such treatment.15. A method for effecting regression of atherosclerotic plaquecomprising administering a therapeutically effective amount of acompound of claim 1 to a patient in need of such treatment.
 16. A methodfor preventing or reducing the risk of atherosclerotic plaque rupturecomprising administering a prophylactically effective amount of acompound of claim 1 to a patient having atherosclerotic plaque.
 17. Apharmaceutical composition comprised of a compound of claim 1 and apharmaceutically acceptable carrier.
 18. A pharmaceutical compositioncomprised of a compound of claim 1, a lipid altering compound and apharmaceutically acceptable carrier.